Formula Milk Versus Donor Breast Milk For Feeding Preterm or Low Birth Weight Infants (Review)

Formula milk versus donor breast milk for feeding preterm or low birth weight infants (Review)
Quigley M, Henderson G, Anthony MY, McGuire W
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 2 http://www.thecochranelibrary.com
Formula milk versus donor breast milk for feeding preterm or low birth weight infants (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Formula milk versus donor breast milk, Outcome 1 Time to regain birth weight (days from birth). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Formula milk versus donor breast milk, Outcome 2 Short term weight change (g/kg/day). Analysis 1.3. Comparison 1 Formula milk versus donor breast milk, Outcome 3 Short term change in crown-heel length (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Formula milk versus donor breast milk, Outcome 4 Short term change in crown-rump length (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Formula milk versus donor breast milk, Outcome 5 Short term change in femoral length (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Formula milk versus donor breast milk, Outcome 6 Short term change in head circumference (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Formula milk versus donor breast milk, Outcome 7 Weight (kg) at 9 months post term. Analysis 1.8. Comparison 1 Formula milk versus donor breast milk, Outcome 8 Length (cm) at 9 months post term. Analysis 1.9. Comparison 1 Formula milk versus donor breast milk, Outcome 9 Head circumference (cm) at 9 months post term. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.10. Comparison 1 Formula milk versus donor breast milk, Outcome 10 Weight (kg) at 18 months post term. Analysis 1.11. Comparison 1 Formula milk versus donor breast milk, Outcome 11 Length (cm) at 18 months post term. Analysis 1.12. Comparison 1 Formula milk versus donor breast milk, Outcome 12 Head circumference (cm) at 18 months post term. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.13. Comparison 1 Formula milk versus donor breast milk, Outcome 13 Weight (kg) at 7.5-8 years of age. Analysis 1.14. Comparison 1 Formula milk versus donor breast milk, Outcome 14 Length (cm) at 7.5-8 years of age. Analysis 1.15. Comparison 1 Formula milk versus donor breast milk, Outcome 15 Head circumference (cm) at 7.5-8 years of age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.16. Comparison 1 Formula milk versus donor breast milk, Outcome 16 Bayley mental development index at 18 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.17. Comparison 1 Formula milk versus donor breast milk, Outcome 17 Bayley psychomotor development index at 18 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.18. Comparison 1 Formula milk versus donor breast milk, Outcome 18 Neurological impairment at 18 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.19. Comparison 1 Formula milk versus donor breast milk, Outcome 19 Mortality. . . . . . . . . Analysis 1.20. Comparison 1 Formula milk versus donor breast milk, Outcome 20 Necrotising enterocolitis. . . . Analysis 1.21. Comparison 1 Formula milk versus donor breast milk, Outcome 21 Suspected necrotising enterocolitis. Analysis 1.22. Comparison 1 Formula milk versus donor breast milk, Outcome 22 Feed intolerance or diarrhoea. . Analysis 1.23. Comparison 1 Formula milk versus donor breast milk, Outcome 23 Incidence of invasive infection. . Analysis 2.1. Comparison 2 Term formula versus donor breast milk, Outcome 1 Short term weight change (g/kg/day). Analysis 2.2. Comparison 2 Term formula versus donor breast milk, Outcome 2 Short term change in crown-heel length (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 1 2 2 2 3 4 9 9 10 10 12 20 22 23 24 24 25 25 26 26 27 27 28 28 29 29 30 30 31 31 32 32 33 33 34 34 35
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Analysis 2.3. Comparison 2 Term formula versus donor breast milk, Outcome 3 Short term change in head circumference (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.4. Comparison 2 Term formula versus donor breast milk, Outcome 4 Necrotising enterocolitis. . . . . Analysis 2.5. Comparison 2 Term formula versus donor breast milk, Outcome 5 Feed intolerance or diarrhoea. . . Analysis 3.1. Comparison 3 Preterm formula versus donor breast milk, Outcome 1 Short term weight change (g/kg/day). Analysis 3.2. Comparison 3 Preterm formula versus donor breast milk, Outcome 2 Short term change in crown-heel length (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.3. Comparison 3 Preterm formula versus donor breast milk, Outcome 3 Short term change in head circumference (mm/week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.4. Comparison 3 Preterm formula versus donor breast milk, Outcome 4 Necrotising enterocolitis. . . . Analysis 3.5. Comparison 3 Preterm formula versus donor breast milk, Outcome 5 Feed intolerance or diarrhoea. . Analysis 4.1. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 1 Short term weight change (g/kg/day). . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.2. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 2 Short term change in crown-heel length (mm/week). . . . . . . . . . . . . . . . . . . . . . . Analysis 4.3. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 3 Short term change in head circumference (mm/week). . . . . . . . . . . . . . . . . . . . . . . Analysis 4.4. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 4 Necrotising enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.1. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 1 Short term weight change (g/kg/day). . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.2. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 2 Short term change in crown-heel length (mm/week). . . . . . . . . . . . . . . . . . . . . Analysis 5.3. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 3 Short term change in head circumference (mm/week). . . . . . . . . . . . . . . . . . . . Analysis 5.4. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 4 Mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.5. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 5 Necrotising enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.6. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 6 Suspected necrotising enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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[Intervention Review]
Formula milk versus donor breast milk for feeding preterm or low birth weight infants
Maria Quigley1 , Ginny Henderson2 , Mary Y Anthony3 , William McGuire4
1 National
Perinatal Epidemiology Unit, University of Oxford, Oxford, UK. 2 School of Nursing and Midwifery, Grifth University, South Brisbane, Australia. 3 Special Care Baby Unit, John Radcliffe Hospital, Headington, UK. 4 Department of Paediatrics and Child Health, Australian National University Medical School, Canberra, Australia
Contact address: Maria Quigley, National Perinatal Epidemiology Unit, University of Oxford, Old Road Campus, Oxford, 0X3 7LF, UK. Maria.Quigley@npeu.ox.ac.uk. (Editorial group: Cochrane Neonatal Group.) Cochrane Database of Systematic Reviews, Issue 2, 2009 (Status in this issue: Unchanged) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: 10.1002/14651858.CD002971.pub2 This version rst published online: 17 October 2007 in Issue 4, 2007. Last assessed as up-to-date: 17 June 2007. (Help document - Dates and Statuses explained) This record should be cited as: Quigley M, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD002971. DOI: 10.1002/14651858.CD002971.pub2.
ABSTRACT Background When sufcient maternal breast milk is not available, the alternative sources of enteral nutrition for preterm or low birth weight infants are donor breast milk or articial formula milk. Feeding preterm or low birth weight infants with formula milk might increase nutrient input and growth rates. However, since feeding with formula milk may be associated with a higher incidence of feeding intolerance and necrotising enterocolitis, this may adversely affect growth and development. Objectives To determine the effect of formula milk compared with donor human breast milk on growth and development in preterm or low birth weight infants. Search strategy The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - May 2007), EMBASE (1980 - May 2007), CINAHL (1982 - May 2007), conference proceedings, and previous reviews. Selection criteria Randomised controlled trials comparing feeding with formula milk versus donor breast milk in preterm or low birth weight infants. Data collection and analysis Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two reviewer authors, and synthesis of data using relative risk, risk difference and weighted mean difference. Main results Eight trials fullled the inclusion criteria. Only one trial used nutrient-fortied donor breast milk. Enteral feeding with formula milk compared with donor breast milk resulted in higher rates of growth in the short term. There was no evidence of an effect on long-term
Formula milk versus donor breast milk for feeding preterm or low birth weight infants (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
growth rates or neurodevelopmental outcomes. Meta-analysis of data from ve trials demonstrated a statistically signicantly higher incidence of necrotising enterocolitis in the formula fed group: typical relative risk 2.5 (95% condence interval 1.2, 5.1); typical risk difference: 0.03 (95% condence interval 0.01, 0.06; number needed to harm: 33 (95% condence interval 17, 100). Authors conclusions In preterm and low birth weight infants, feeding with formula milk compared with donor breast milk results in a higher rate of shortterm growth but also a higher risk of developing necrotising enterocolitis. There are only limited data on the comparison of feeding with formula milk versus nutrient-fortied donor breast milk. This limits the applicability of the ndings as nutrient fortication of breast milk is now a common practice in neonatal care. Future trials may compare growth, development and adverse outcomes in infants who receive formula milk versus nutrient-fortied donor breast milk given as a supplement to maternal expressed breast milk or as a sole diet.
PLAIN LANGUAGE SUMMARY Formula milk versus donor breast milk for feeding preterm or low birth weight infants When a mothers own breast milk is not available for feeding her preterm or low birth weight infant, the alternatives are either formula milk or expressed breast milk from a donor mother (donor breast milk). Review of eight randomised controlled trials suggests that feeding with formula increases short-term growth rates but is associated with a higher risk of developing the severe gut disorder necrotising enterocolitis. There is no evidence of an effect on longer-term growth, or on development. Further trials that compare these two strategies are needed. These should probably compare formula milk adapted for preterm infants with donor breast milk supplemented with nutrients.
BACKGROUND
Maternal breast milk is the recommended form of enteral nutrition for preterm or low birth weight infants (AAP 1997). However, sufcient maternal breast milk is not always available. The two common alternatives available for feeding preterm or low birth weight infants are formula milk and donor breast milk. A variety of formula milks (usually modied cow milk) are available. These vary in energy, protein and mineral content but, broadly, can be considered as: (a) Term formulae; designed for term infants, based on the composition of mature breast milk. The typical energy content is between about 67 to 70 kilocalories per 100 millilitres. (b) Preterm formulae; designed to provide nutrient intakes to match intra-uterine accretion rates (Tsang 1993). These are energy-enriched (typically up to about 80 kilocalories per 100 millilitres), and variably protein- and mineral-enriched (Fewtrell 1999). Expressed breast milk from donor mothers, usually mothers who have delivered at term, generally has a lower content of energy and protein than term formula milk (Gross 1980; Gross 1981). The nutritional quality of donor breast milk may be further compromised by Pasteurisation (Wight 2001). Donor human milk varies with regard to fat, energy and protein content depending upon the stage of lactation at which it is collected. Milk expressed from the donors lactating breast has a higher energy and protein content than that collected from the contralateral breast (drip breast milk) (Lucas 1978). There is concern that the nutritional requirements of preterm or low birth weight infants, who are born with relatively impoverished nutrient reserves and are subject to additional metabolic stresses compared with term infants, may not be fully met by enteral feeding with donor human milk (Hay 1994; Schanler 1995). These deciencies may have adverse consequences for growth and development. However, a major putative benet of donor breast milk is that the delivery of immunoprotective and growth factors to the immature gut mucosa may prevent serious adverse outcomes, including necrotising enterocolitis and invasive infection (Beeby 1992; Lucas 1990).
OBJECTIVES
To examine the effect of enteral feeding with formula milk versus donor breast milk on growth, developmental outcomes, and adverse events, including feed tolerance, necrotising enterocolitis, and invasive infection, in preterm or low birth weight infants. Subgroup analyses:
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1. Term formula milk (containing up to 72 kilocalories per 100 millilitres) versus donor human milk. 2. Preterm formula milk (containing more than 72 kilocalories per 100 millilitres) versus donor human milk. 3. Formula milk given as a sole diet versus donor breast milk given as a sole diet. 4. Formula milk given as a supplement to maternal breast milk versus donor breast milk given as a supplement to maternal breast milk. 5. Formula milk versus nutrient-fortied donor breast milk (dened as supplementation with more than one of the following components: protein, fat, carbohydrate, or minerals).
METHODS
Criteria for considering studies for this review

Types of studies Controlled trials utilizing either random or quasi-random patient allocation. Types of participants Preterm (less than 37 weeks gestation) or low birth weight (less than 2.5 kilograms) infants. Types of interventions Enteral feeding with formula milk versus donor breast milk. The allocated milk feed may form the entire enteral intake or be a supplement to maternal breast milk. Trials in which parenteral nutritional support is available during the period of advancement of enteral feeds are acceptable provided that the groups receive similar treatment other than the type of milk feed. Types of outcome measures Primary: 1. Growth: (i) Rates of weight gain (grams per day, or grams per kilogram per day), linear growth (millimetres per week), head growth (millimetres per week), or skinfold thickness growth (millimetres per week) during the trial period. (ii) Long-term growth- weight, height, or head circumference (and/or proportion of infants who remain below the tenth percentile for the index populations distribution) assessed at intervals from 6 months of age (corrected for preterm birth), to 18 months, and beyond. 2. Development:
(i) Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools. (ii) Severe neurodevelopmental disability dened as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70 or more than two standard deviations below the mean), severe auditory impairment (sensorineural deafness requiring (or too severe to (benet from) hearing aids) or visual impairment (legal blindness). When available, each component was analyzed individually as well as part of the composite outcome. (iii) Cognitive and educational outcomes at aged more than 5 years old: Intelligence quotient and/or indices of educational achievement measured using a validated assessment tool (including school examination results). Secondary: 1. Death in the neonatal period (up to 28 days) and death prior to hospital discharge. 2. Necrotising enterocolitis conrmed by at least two of the following features: Abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen; abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both); blood in stool; lethargy, hypotonia, or apnea (or combination of these); or a diagnosis conrmed at surgery or autopsy. 3. Time after birth to establish full enteral feeding (independently of parenteral nutrition) (days). 4. Feeding intolerance dened as a requirement to cease enteral feeds and commence parenteral nutrition. 5. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebro-spinal uid, urine, or from a normally sterile body space.
Search methods for identication of studies

See: Collaborative Review Group search strategy The standard search strategy of the Cochrane Neonatal Review Group was used. This consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966- May 2007), and EMBASE (1980 - May 2007), and CINAHL (1982- May 2007). The electronic search used the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR infan* OR neonat*] AND Infant-Nutrition/ all subheadings OR Infant Formula OR milk OR formula]. The search outputs were limited with the relevant lters for clinical trials. No language restriction was applied. References in previous reviews and in studies identied as potentially relevant were examined. The abstracts presented at the annual scientic meetings of the Society for Pediatric Research, the European Society for Pediatric Research from 1980 until 2004 were hand searched. Trials that had been reported only as abstracts
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were eligible for inclusion if sufcient information was available from the report, or from contact with the authors, to full the inclusion criteria.
2005; Schultz 1980; Tyson 1983; see table, Characteristics of Included Studies). Most of the included studies were undertaken during the late 1970s and early 1980s by investigators attached to neonatal units in Europe and North America. One trial has been undertaken since the year 2000 (Schanler 2005). Participants 1017 infants in total participated in the included trials. Most participants were clinically stable preterm infants of gestational age less than about 32 weeks, and/or birth weight less than about 1800 grams. Most of the trials specically excluded infants who were small for gestational age at birth and infants with congenital anomalies, or gastrointestinal or neurological problems. Interventions Four trials compared feeding with term formula milk versus donor breast milk (Davies 1977; Gross 1983; Raiha 1976; Schultz 1980). Four trials compared feeding with preterm formula milk versus donor breast milk (Lucas 1984a; Lucas 1984b; Schanler 2005; Tyson 1983). In two of these trials, preterm formula milk or donor breast milk was given as a supplement to maternal breast milk (Lucas 1984b; Schanler 2005). In general, feeds were allocated for several weeks, or until participating infants reached a specied weight (generally above about 2 kg). In all trials, except one ( Tyson 1983), the donor breast milk was pasteurised. None of the trials, except the most recent study (Schanler 2005), used nutrientfortied donor breast milk. Five trials used donor breast milk collected from mothers who had delivered an infant at term (Davies 1977; Lucas 1984a; Lucas 1984b; Raiha 1976; Schultz 1980). Two of these trials used drip breast milk (Lucas 1984a; Lucas 1984b). One trial used preterm milk (Schanler 2005), one trial used both term and preterm milk (Gross 1983) and one trial did not specify the type of donor breast milk (Schanler 2005). Outcomes The most commonly reported outcomes were growth parameters during the study period. Most reports also gave information on adverse outcomes, including feed intolerance and necrotising enterocolitis. Only two trials reported long term-growth and neurodevelopmental outcomes for surviving infants (Lucas 1984a; Lucas 1984b).
Data collection and analysis

1. The title and abstract of all studies identied by the above search strategy were screened by two review authors. The full text of any potentially eligible reports was re-assessed and those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were discussed until consensus was achieved. 2. The criteria and standard methods of the Cochrane Neonatal Review Group were used to independently assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or carers and assessors to intervention, and completeness of assessment in all randomised individuals. Additional information from the trial authors was requested to clarify methodology and results as necessary. 3. A data collection form was used to aid extraction of relevant information from each included study. Two review authors extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufcient, the trialists were contacted for further information. 4. Outcomes for categorical data are presented as relative risk, risk difference, and number needed to treat, with respective 95% condence intervals. For continuous data, the weighted mean difference with 95% condence interval was used. 5. The treatment effects of individual trials and heterogeneity between trial results were examined by inspecting the forest plots. The impact of heterogeneity in any meta-analysis was assessed using a measure of the degree of inconsistency in the studies results (I- squared statistic). If statistical heterogeneity was noted, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using post-hoc subgroup analyses. A xed effects model for metaanalyses was used.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies. Fourteen trials that appeared to be relevant were identied in the rst round of screening. Six studies were excluded and these are detailed in the table, Characteristics of Excluded Studies (Cooper 1984; Jarvenpaa 1983; Narayanan 1982; OConnor 2003; Putet 1984; Svenningsen 1982). Eight trials were included (Davies 1977; Gross 1983; Lucas 1984a; Lucas 1984b; Raiha 1976; Schanler
Risk of bias in included studies

Quality assessments are detailed in the table, Characteristics of Included Studies. In general, methodological quality was fair. The earliest trials did not provide details of the randomisation procedures (Davies 1977; Raiha 1976; Schultz 1980). The other trials used methods of randomisation likely to ensure adequate allocation concealment. Only one of the trials blinded parents, caregivers or assessors prior to hospital discharge (Schanler 2005). In Lucas 1984a and Lucas 1984b, the assessment of long term out4
comes in infants was undertaken blind to the dietary intervention. All of the trials achieved complete or near-complete follow up.
Effects of interventions
FORMULA MILK VS. DONOR BREAST MILK (Comparison 01): Primary outcomes: 1. Growth (Outcomes 01.01 - 01.15): Time to regain birth weight was reported by ve trials. Gross 1983 reported mean time to regain birth weight as statistically signicantly lower in the formula fed group, excluding those randomised, but subsequently withdrawn because of feeding intolerance or necrotising enterocolitis (10.3 vs. 15.1 days). Raiha 1976 did not nd a statistically signicant difference (13.5 vs. 16.3 days). Meta-analysis of these data found that the formula fed group regained birth weight more quickly: Weighted mean difference: -4.0 days (95% condence interval -5.8, -2.2). Schultz 1980 reported the mean time to regain birth weight as 2.5 weeks in the formula fed group, compared with 1.5 weeks in the human milk fed group. This was stated to be a non-signicant difference. However, standard deviations were not reported and the data could not be included in the meta-analysis. Lucas 1984a reported the median time to regain birth weight as statistically signicantly lower in the formula fed infants (10 vs. 16 days). Lucas 1984b did not nd a statistically signicantly difference (13 vs. 15 days). However, in both these trials, standard deviations were not reported and the data were not included in the meta-analysis. Weight gain rates were reported by eight trials. Davies 1977 did not nd a statistically signicant difference in the rate of weight gain from birth to two months. Gross 1983 reported a statistically signicantly higher rate of weight gain, from the point of regained birth weight until attaining a weight of 1800 grams, in the formula fed group of infants. Lucas 1984a and Lucas 1984b reported statistically signicantly higher rates of weight gain from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 grams in the formula fed group of infants. Raiha 1976 reported a statistically signicantly higher rate of weight gain in the formula fed infants from the point of regained birth weight until attaining a weight of 2400 grams. Schanler 2005 found a statistically signicantly higher rate of weight gain during the study period in the formula fed group. Schultz 1980 did not nd a statistically signicant difference in the rate of weight gain from the point of regained birth weight but numerical data were not reported (or available from the authors). Tyson 1983 reported a statistically signicantly higher rate of weight gain from the point of entry into the trial (day 10) until day 30 in the formula fed group of infants. Meta-analysis of data from the seven trials that provided numerical data found a statistically signicantly higher rate of weight gain in the formula fed group: Weighted mean difference: 2.6 grams per kilogram per day (95% condence interval
2.0, 3.2). There was statistically signicant heterogeneity of effect in this meta-analysis. Linear growth rates were reported by seven trials. Davies 1977; Gross 1983; and Schanler 2005 did not nd any statistically signicant difference in the rate of increase in crown-heel length. The other trials reported statistically signicantly greater rates of increase in crown-heel length in the formula fed infants (Lucas 1984a; Lucas 1984b; Tyson 1983). Meta-analysis of the data from these six trials demonstrated a statistically signicantly greater rate of increase in crown-heel length in the formula fed group: Weighted mean difference: 1.1 mm/week (95% condence interval 0.6, 1.7). There was statistically signicant heterogeneity of effect in this meta-analysis. Raiha 1976 reported statistically signicantly greater rates of increase in crown-rump length [mean difference: 0.6 mm/week (95% condence interval 0.1, 1.1)] and femoral length [mean difference: 0.4 mm/week (95% condence interval 0.2, 0.6)] in the formula fed infants. Head growth was reported by six trials. Three trials did not nd any statistically signicant difference in the rate of increase in occiptofrontal head circumference (Davies 1977; Lucas 1984b; Schanler 2005). Three trials found a statistically signicantly greater rate of increase in occipto-frontal head circumference in the formula fed infants (Gross 1983; Lucas 1984a; Tyson 1983). Meta-analysis of the data from these six reports demonstrated a statistically signicantly higher rate of increase in occipto-frontal head circumference in the formula fed group: Weighted mean difference: 1.2 mm/week (95% condence interval 0.7, 1.7). There was statistically signicant heterogeneity of effect in this meta-analysis. Long-term growth data were reported by Lucas 1984a and Lucas 1984b. Neither individual study, nor meta-analyses of data from both studies, found any statistically signicant differences in the weight, length, or head circumference at 9 months, 18 months, or 7.5- 8 years post-term. Development (Outcomes 01.16 - 01.18): Neurodevelopmental outcomes were reported by two trials. Neither Lucas 1984a nor Lucas 1984b, nor a meta-analysis of data from both, found statistically signicant differences in Bayley Psychomotor and Mental Development Indices at 18 months corrected age. Bayley Mental Development Index: Weighted mean difference 1.24 (95% condence interval -2.6, 5.1). Bayley Psychomotor Development Index: Weighted mean difference -0.3 (95% condence interval 3.8, 3.9). Long-term neurodevelopmental data were not reported by Gross 1983. However, a subsequent report (only in abstract form) stated that, at 15 months corrected age, both groups had similar patterns of growth and no difference in Bayley Mental or Psychomotor Developmental Indices. Severe neurodevelopmental disability (Ameil-Tison 1986 classication) was assessed in two trials. Neither Lucas 1984a nor Lucas 1984b, nor a metaanalysis of data from both studies, demonstrated a statistically signicant difference in the incidence of neurological impairment at 18 months post term: typical relative risk: 1.2 (95% condence interval 0.6, 2.3); typical risk difference: -0.02 (95% condence
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interval -0.04, 0.17). Cognitive and educational outcomes were not reported by any of the trials. Secondary outcomes: Mortality (Outcome 01.19): Data were available from three trials. Two trials reported mortality until 9 months corrected for preterm delivery (Lucas 1984a; Lucas 1984b). The third trial reported mortality until hospital discharge (Schanler 2005). None of the studies found a statistically signicant difference. Since it is likely that most infant mortality in this population occurred before hospital discharge, the data from all three trials was combined in a meta-analysis. This analysis did not demonstrate a statistically signicant difference: typical relative risk 1.2 (95% condence interval 0.7, 2.1); typical risk difference: 0.02 (95% condence interval -0.02, 0.05). Necrotising enterocolitis (Outcomes 01.20 - 01.21): Reported as an outcome by ve trials (Gross 1983; Lucas 1984a; Lucas 1984b; Schanler 2005; Tyson 1983). None found a statistically signicant difference. Meta-analysis of data from the ve trials demonstrated a statistically signicantly higher incidence of necrotising enterocolitis in the formula fed group: typical relative risk 2.5 (95% condence interval 1.2, 5.1); typical risk difference: 0.03 (95% condence interval 0.01, 0.06; number needed to harm: 33 (95% condence interval 17, 100). Lucas 1984a; Lucas 1984b; and Tyson 1983 also reported the incidence of suspected necrotising enterocolitis, that is, necrotising enterocolitis including cases with consistent clinical features but without radiological, surgical, or autopsy conrmation. Neither individual study, nor a metaanalysis of data from the three studies, found a statistically signicant difference: typical relative risk: 1.4 (95% condence interval 0.7, 2.7); typical risk difference: 0.02 (95% condence interval 0.02, 0.06). Time after birth to establish full enteral feeding: Not reported by any of the included trials. Lucas 1984a reported that signicantly more infants in the formula fed group failed to tolerate full enteral feeds by two weeks after birth (25/76 vs. 9/83), and by three weeks after birth (13/76 vs. 4/83). Feed intolerance (Outcome 01.22): Reported by two trials. Gross 1983 reported a statistically signicantly higher rate of feed intolerance in the formula fed group. Tyson 1983 did not detect a significant difference. Meta-analysis demonstrated a statistically signicant higher risk of feed intolerance in the formula fed group: typical relative risk: 4.9 (95% condence interval 1.2, 20.7); typical risk difference: 0.1 (95% condence interval 0.01, 0.19). Schultz 1980 reported cases of mild diarrhoea, but these do not appear to have been clinically important and have not been included in the analysis. Invasive infection (Outcome 01.23): Reported by one trial. Schanler 2005 did not nd a statistically signicant difference in the incidence (one or more episodes) of invasive infection: relative risk: 0.97 (95% condence interval 0.66, 1.44); risk difference: 0.01 (95% condence interval -0.16, 0.14).
SUBGROUP ANALYSES: TERM FORMULA MILK VS. DONOR BREAST MILK (Comparison 02): In all four trials (Davies 1977; Gross 1983; Raiha 1976; Schultz 1980), the formula and donor breast milk was given as a sole diet. Primary outcomes: Growth (Outcomes 02.01 - 02.03): Time to regain birth weight was reported by three trials. Meta-analysis of data from two trials found that the formula fed group regained birth weight more quickly: Weighted mean difference: -4.0 days (95% condence interval -5.8, -2.2) (Gross 1983; Raiha 1976). Schultz 1980 did not nd a statistically signicant difference but standard deviations were not reported and the data could not be included in the metaanalysis. Weight gain rates were reported by four trials. Meta-analysis of the data from three trials found that the formula fed group had a statistically signicantly greater rate of weight gain: Weighted mean difference: 1.7 grams per kilogram per day (95% condence interval 1.0, 2.5) (Davies 1977; Gross 1983; Raiha 1976). Schultz 1980 did not nd any statistically signicant difference but numerical data for inclusion in the meta-analysis were not reported. Linear growth rates were reported by three trials. Davies 1977 and Gross 1983 did not nd statistically signicantly differences but meta-analysis of the studies demonstrated a statistically signicantly greater rate of increase in crown-heel length in the formula fed group: Weighted mean difference: 0.8 mm/week (95% condence interval 0.1, 1.5). Raiha 1976 reported statistically signicantly greater rates of increase in crown-rump length [mean difference: 0.6 mm/week (95% condence interval 0.1, 1.1)], and femoral length [mean difference: 0.4 mm/week (95% condence interval 0.2, 0.6)] in the formula fed infants (see 01.05- 01.06). Head growth was reported by two trials. Meta-analysis demonstrated a statistically signicantly higher rate of increase in occiptofrontal head circumference in the formula fed group: Weighted mean difference: 0.8 mm/week (95% condence interval 0.1, 1.5) (Davies 1977; Gross 1983). Long-term growth parameters were not reported by any of the trials. 2. Development: Neurodevelopmental outcomes were not reported by any of the trials. Secondary outcomes: Mortality: not reported by any of the trials. Necrotising enterocolitis (Outcome 02.04): Reported as an outcome by one trial. Gross 1983 did not nd a statistically signicant difference: relative risk 4.7 (95% condence interval 0.5, 43.1); typical risk difference: 0.09 (95% condence interval -0.04, 0.22). Time after birth to establish full enteral feeding: Not reported by any of the trials. Feed intolerance (Outcome 02.05): Reported by one trial. Gross 1983 reported a statistically signicantly higher rate of feed intolerance in the formula fed group: relative risk: 9.5 (95% condence interval 1.2, 74.2); risk difference: 0.21 (95% condence interval
6
0.04, 0.38). Invasive infection: Not reported by any of the trials. SUBGROUP ANALYSES: PRETERM FORMULA MILK VS. DONOR BREAST MILK (Comparison 03): These trials varied with respect to the type of donor breast milk and whether the formula or donor breast milk was given as a sole or a supplement to maternal breast milk (Lucas 1984a Lucas 1984b; Schanler 2005; Tyson 1983). Primary outcomes: Growth (Outcomes 03.01 - 03.03): Time to regain birth weight was reported by two trials. Lucas 1984a reported the median time to regain birth weight as statistically signicantly lower in the formula fed infants (10 vs. 16 days). Lucas 1984b did not nd a statistically signicantly difference (13 vs. 15 days). Neither trial reported standard deviations so the data could not be included in a meta-analysis. Weight gain rates were reported in four trials. All of the individual trials, and a meta-analysis of the data, found a statistically signicantly greater rate of weight gain in the formula fed group of infants: Weighted mean difference: 3.8 grams per kilogram per day (95% condence interval 2.9, 4.8) (Tyson 1983; Lucas 1984a; Lucas 1984b; Schanler 2005). Linear growth rates were reported by four trials. Meta-analysis of the data from the four trials demonstrated a statistically signicantly greater rate of increase in crown-heel length in the formula fed group: Weighted mean difference: 1.6 mm/week (95% condence interval 0.8, 2.4) (Lucas 1984a; Lucas 1984b; Schanler 2005; Tyson 1983). Head growth was reported by four trials. Meta-analysis of the data from the trials demonstrated a statistically signicantly higher rate of increase in occipto-frontal head circumference in the formula fed group: Weighted mean difference: 1.8 mm/week (95% condence interval 1.1, 2.6) (Lucas 1984b; Lucas 1984a;Schanler 2005; Tyson 1983). Long-term growth data were reported by two trial (Lucas 1984a; Lucas 1984b; see above). Development: Neurodevelopmental outcomes were reported by two trials (Lucas 1984a; Lucas 1984b; see above). Secondary outcomes: Mortality: Data were available from three trials (Lucas 1984a; Lucas 1984b; Schanler 2005- see 01.19 and above). Necrotising enterocolitis (Outcome 03.04): Reported as an outcome by four trials (03.07). Meta-analysis of data from the trials demonstrated a borderline statistically signicantly higher incidence of necrotising enterocolitis in the formula fed group: typical relative risk 2.26 (95% condence interval 1.04, 4.90); typical risk difference: 0.03 (95% condence interval 0.00, 0.06) (Lucas 1984a; Lucas 1984b; Schanler 2005; Tyson 1983). Time after birth to establish full enteral feeding: Not reported by any of the included trials.
Feed intolerance (Outcome 03.05): Reported by one trial. Tyson 1983 did not detect a signicant difference in the incidence of feed intolerance: relative risk: 1.7 (95% condence interval 0.2, 17.8); risk difference: 0.02 (95% condence interval -0.06, 0.10). Invasive infection (see Outcome 01.24): Schanler 2005 did not nd a statistically signicant difference in the incidence of (one or more episodes of ) invasive infection: relative risk: 0.97 (95% condence interval 0.66, 1.44); risk difference: -0.01 (95% condence interval -0.16, 0.14). SUBGROUP ANALYSES: FORMULA MILK GIVEN AS A SOLE DIET VS. DONOR BREAST MILK GIVEN AS A SOLE DIET (Comparison 04): Davies 1977; Gross 1983; Lucas 1984a; Raiha 1976; Schultz 1980; Tyson 1983): Primary outcomes: Growth (Comparisons 04.01 - 04.03): Time to regain birth weight was reported by four trials. Meta-analysis of the two trials found that the formula fed group regained birth weight more quickly: Weighted mean difference: -4.0 days (95% condence interval -5.8, -2.2) (Gross 1983; Raiha 1976). Schultz 1980 did not nd a statistically signicant difference. Lucas 1984a reported that the median time to regain birth weight was statistically signicantly lower in the formula fed infants. In both these trials, standard deviations were not reported and the data could not be included in the meta-analysis. Weight gain rates were reported in six trials (Davies 1977; Gross 1983; Lucas 1984a; Raiha 1976; Schultz 1980; Tyson 1983). Meta-analysis of data from ve trials that provided numerical data found a statistically signicantly higher rate of weight gain in the formula fed group: Weighted mean difference: 2.7 grams per kilogram per day (95% condence interval 2.0, 3.4). Schultz 1980 did not nd any statistically signicant difference in the rate of weight gain but numerical data were not reported. Linear growth rates were reported by ve trials. Meta-analysis of the data from four of these trials demonstrated a statistically signicantly greater rate of increase in crown-heel length in the formula fed group Weighted mean difference: 1.3 mm/week (95% condence interval 0.7, 1.9) (Davies 1977; Gross 1983; Lucas 1984a; Tyson 1983). Raiha 1976 reported statistically signicantly greater rates of increase in crown-rump length [mean difference: 0.6 mm/week (95% condence interval 0.1, 1.1)] and femoral length [mean difference: 0.4 mm/week (95% condence interval 0.2, 0.6)] in the formula fed infants. Head growth was reported by four trials: Meta-analysis of the data from these four trials demonstrated a statistically signicantly higher rate of increase in occipto-frontal head circumference in the formula fed group: Weighted mean difference: 1.4 mm/week (95% condence interval 0.9, 2.0) (Davies 1977; Gross 1983; Lucas 1984a; Tyson 1983). Long-term growth data were reported by Lucas 1984a. The trial
7
did not detect any statistically signicant differences in the weight, length, or head circumference at 9 months, 18 months, or 7.5- 8 years post-term. Development: Neurodevelopmental outcomes were reported by Lucas 1984a (see above). The trial did not nd any statistically signicant differences in Bayley Psychomotor and Mental Development Indices, nor in the incidence of neurological impairment, at 18 months corrected age. Numerical data on long term neurodevelopment were not reported by Gross 1983. At 15 months corrected age, both groups had similar patterns of growth and no difference in Bayley Mental or Psychomotor Developmental Indices. Cognitive and educational outcomes were not reported by any of the trials. Secondary outcomes: Mortality: Data were available from one trial (see above). Lucas 1984a did not nd a statistically signicant difference: relative risk 1.4 (95% condence interval 0.5, 3.6); risk difference: 0.03 (95% condence interval -0.06, 0.13) Necrotising enterocolitis (Outcome 04.03): Reported by three trials. Meta-analysis of data demonstrated a borderline statistically signicantly higher incidence of necrotising enterocolitis in the formula fed group: typical relative risk 4.0 (95% condence interval 1.0, 16.2); typical risk difference: 0.05 (95% condence interval 0.00, 0.09) (Gross 1983; Lucas 1984a; Tyson 1983). Time after birth to establish full enteral feeding: Not reported by any of the included trials. Lucas 1984a reported that signicantly more infants in the formula fed group failed to tolerate full enteral feeds by two weeks after birth (25/76 vs. 9/83), and by three weeks after birth (13/76 vs. 4/83). Feed intolerance: Reported by two trials (see above). Gross 1983 reported a statistically signicantly higher rate of feed intolerance in the formula fed group. Tyson 1983 did not detect a signicant difference. Meta-analysis demonstrated a statistically signicant higher risk of feed intolerance in the formula fed group: typical relative risk: 4.9 (95% condence interval 1.2, 20.7); typical risk difference: 0.1 (95% condence interval 0.01, 0.19). Invasive infection: Not reported by any of the trials. SUBGROUP ANALYSES: FORMULA MILK GIVEN AS A SUPPLEMENT TO MATERNAL BREAST MILK VS. DONOR BREAST MILK GIVEN AS A SUPPLEMENT TO MATERNAL BREAST MILK (Comparison 05): Both trials used preterm formula (Lucas 1984b; Schanler 2005). Primary outcomes: Growth (Outcomes 05.01 - 05.03): Time to regain birth weight was reported by one trial. Lucas 1984b did not nd a statistically signicantly difference (13 vs. 15 days). Standard deviations were not reported. Weight gain rates were reported in both trials. Lucas 1984b and Schanler 2005 both reported a statistically signicantly greater rate of weight gain in the formula fed group of infants: Weighted
mean difference: 2.4 grams per kilogram per day (95% condence interval 1.3, 3.5). Linear growth rates were reported in both trials. Lucas 1984b reported statistically signicantly greater rates of increase in crownheel length in the formula fed infants. Schanler 2005 did not nd any statistically signicant difference. Meta-analysis of the data from the two trials did not nd a statistically signicantly difference: Weighted mean difference: 0.7 mm/week (95% condence interval -0.3, 1.8). Head growth was reported by two trials. Neither Lucas 1984b nor Schanler 2005, nor meta-analysis of the two trials found a statistically signicant difference: Weighted mean difference: 0.6 mm/week (95% condence interval -0.4, 1.6). Long-term growth data were reported by one trial (see above). Lucas 1984b did not nd any statistically signicant differences in the weight, length, or head circumference at 9 months, 18 months, or 7.5- 8 years post-term. Development: Neurodevelopmental outcomes were reported by one trial (see above). Lucas 1984b did not nd any statistically signicant differences in Bayley Psychomotor and Mental Development Indices or in the incidence of neurological impairment at 18 months corrected age. Secondary outcomes: Mortality (Outcome 05.04): Data were available from two trials. Neither Lucas 1984b nor Schanler 2005, nor meta-analysis of the two trials found a statistically signicant difference: typical relative risk 1.2 (95% condence interval 0.6, 2.2); typical risk difference: 0.01 (95% condence interval -0.03, 0.05). Necrotising enterocolitis (see Outcomes 03.05- 03.06): Reported as an outcome by two trials . Neither Lucas 1984b nor Schanler 2005, nor meta-analysis of the two trials found a statistically signicant difference: typical relative risk 2.0 (95% condence interval 0.8, 4.7); typical risk difference: 0.03 (95% condence interval -0.01, 0.06). One trial also reported incidences including cases of suspected necrotising enterocolitis. Lucas 1984b did not nd a statistically signicant difference: relative risk 1.1 (95% condence interval 0.5, 2.4); risk difference: 0.00 (95% condence interval -0.05, 0.06). Time after birth to establish full enteral feeding: Not reported by any of the included trials. Feed intolerance: Not reported by any of the included trials. Invasive infection: Reported by one trial (Schanler 2005; see above). SUBGROUP ANALYSES: FORMULA MILK VS. NUTRIENT-FORTIFIED DONOR BREAST MILK: Schanler 2005) As only one trial is included in this analysis, a separate comparison was not created. Data discussed below is derived from the report
8
of the individual trial in Table 01. Primary outcomes: Growth: Not reported. Development: Not reported. Secondary outcomes: Mortality: Schanler 2005 did not nd a statistically signicant difference: relative risk 0.9 (95% condence interval 0.2, 4.3); risk difference: 0.00 (95% condence interval -0.06, 0.05). Necrotising enterocolitis:. Schanler 2005 did not nd a statistically signicant difference: relative risk 1.8 (95% condence interval 0.6, 5.0); risk difference: 0.05 (95% condence interval 0.04, 0.14). Time after birth to establish full enteral feeding: Not reported. Feed intolerance: Not reported. Invasive infection: Schanler 2005 did not nd a statistically signicant difference in the incidence of (one or more episodes of ) invasive infection: relative risk: 0.97 (95% condence interval 0.66, 1.44); risk difference: -0.01 (95% condence interval -0.16, 0.14).
However, none of the trials were able to blind caregivers and assessors to the intervention. This methodological weakness may have resulted in surveillance and ascertainment biases that contributed to the higher rate of detection of necrotising enterocolitis in formula-fed infants. It is also unclear whether this putative benet of donor breast milk exists when given as a supplement to maternal breast milk rather than as a sole diet. Meta-analysis of the two trials that examined this comparison did not detect a statistically significant effect (Lucas 1984b; Schanler 2005). Finally, caution should be exercised in applying these data as growth-restricted preterm infants (or sick infants) since this population, although at high risk of developing necrotising enterocolitis, were excluded from the included trials (Dorling 2006). The data in this review are from trials undertaken in resource-rich countries. In resource-poor countries, where the risk of infection in the neonatal period is much higher, the anti-infective properties of breast milk may confer advantages that outweigh the lower rate of short-term growth. In India, a randomised trial in low birth weight infants at risk of infection found that serious infections (diarrhoea, pneumonia, septicaemia) were statistically signicantly less common in infants allocated to received expressed human milk versus formula milk (Narayanan 1982). Expressed human milk in this study referred to a mixture of maternal and donor breast milk. As these could not be separated into sub-groups, the data were not included in the review.
DISCUSSION
These data suggest that preterm or low birth weight infants who receive formula milk regain birth weight earlier and have higher short-term rates of weight gain, linear growth, and head growth than infants who receive donor breast milk. Subgroup analyses found that studies that used preterm formula milk had greater effects on growth parameters than those that used term formula compared with donor breast milk. However, follow-up of the infants who participated in the two largest trials did not nd a signicant effect on long-term growth parameters or neurodevelopmental outcomes (Lucas 1984a; Lucas 1984b). These ndings should be interpreted with caution. Substantial heterogeneity between the studies limits the validity of the pooled estimates of effect size. The trials used different inclusion criteria and varied in terms of the type of formula and donor breast milk used. Furthermore, all of the studies, except one (Schanler 2005), used donor breast milk without any additional nutrient fortication. This limits the applicability of the ndings to current practice where nutrient fortication of breast milk is commonly undertaken (Kuschel 1999; Kuschel 2000a; Kuschel 2000b; Kuschel 2004). Evidence exists that supplementation of human milk with nutrient fortiers increases short term growth rates, but does not appear to affect growth beyond infancy (Kuschel 2004). Meta-analysis of data from ve trials suggests that feeding with formula milk signicantly increases the risk of developing necrotising enterocolitis. The observed effect sizes were similar across the ve studies, and there was no statistical evidence of heterogeneity. The pooled estimate suggests that one extra case of necrotising enterocolitis will occur in every 33 infants who receive formula milk.
AUTHORS CONCLUSIONS Implications for practice

Feeding with formula milk, compared with donor breast milk, leads to higher rates of short-term growth in preterm or low birth weight infants, but is associated with an increased risk of developing necrotising enterocolitis. There are only limited data from randomised trials on the comparison of feeding with formula milk versus nutrient-fortied human milk. This limits the implications for practice of this review as nutrient fortication of human milk is now a common practice in neonatal care.
Implications for research

Further randomised controlled trials are needed to assess the effect of feeding preterm or low birth weight infants with formula milk versus donor breast milk in situations where the expressed breast milk of the infants mother is not consistently available. Future studies should probably compare enteral feeding with formula milk versus nutrient-fortied donor breast milk in a population of infants at increased risk of necrotising enterocolitis, such as very low birth weight infants. Separate comparisons of formula versus donor breast milk as supplements to maternal expressed breast milk and as sole diets are warranted, since their effects may vary. Trials should attempt to ensure that carers and assessors are
9
blind to the intervention. Although more easily achievable for the longer term assessments, this is also important with regard to ascertainment of adverse events, such as feed intolerance and necrotising enterocolitis, where the threshold for investigation or diagnosis may be affected by knowledge of the intervention.
ACKNOWLEDGEMENTS
The UK National Perinatal Epidemiology Unit receives funding from the UK Department of Health. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.
REFERENCES
References to studies included in this review

Davies 1977 {published data only} Davies DP. Adequacy of expressed breast milk for early growth of preterm infants. Archives of Disease in Childhood 1977;52:296301. Gross 1983 {published data only} Gross SJ. Growth and biochemical response of preterm infants fed human milk or modied infant formula. New England Journal of Medicine 1983;308:23741. Lucas 1984a {published data only} Lucas A. AIDS and milk bank closures. Lancet 1987;1(8541):1092 3. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:151923. Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF, Barr I, et al.Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Archives of Disease in Childhood 1984;59:72230. Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Archives of Disease in Childhood 1994;70:F1416. Lucas A, Morley R, Cole TJ, Gore SM, Davis JA, Bamford MF, et al.Early diet in preterm babies and developmental status in infancy. Archives of Disease in Childhood 1989;64:15708. Morley R, Lucas A. Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children. American Journal of Clinical Nutrition 2000;71:8228. Lucas 1984b {published data only} Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:151923. Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF, Barr I, et al.Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Archives of Disease in Childhood 1984;59:72230. Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Archives of Disease in Childhood 1994;70:F1416. Lucas A, Morley R, Cole TJ, Gore SM, Davis JA, Bamford MF, et al.Early diet in preterm babies and developmental status in infancy.
Archives of Disease in Childhood 1989;64:15708. Morley R, Lucas A. Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children. American Journal of Clinical Nutrition 2000;71:8228. Raiha 1976 {published data only} Gaull GE, Rassin DK, Raiha NC, Heinonen K. Milk protein quantity and quality in low-birth-weight infants. III. Effects on sulfur amino acids in plasma and urine. Journal of Pediatrics 1977;90:34855. Raiha NC, Heinonen K, Rassin DK, Gaull GE. Milk protein quantity and quality in low-birthweight infants: I. Metabolic responses and effects on growth. Pediatrics 1976;57:65984. Rassin DK, Gaull GE, Heinonen K, Raiha NC. Milk protein quantity and quality in low-birth-weight infants: II. Effects on selected aliphatic amino acids in plasma and urine. Pediatrics 1977;59:407 22. Rassin DK, Gaull GE, Raiha NC, Heinonen K. Milk protein quantity and quality in low-birth-weight infants. IV. Effects on tyrosine and phenylalanine in plasma and urine. Journal of Pediatrics 1977;90: 35660. Schanler 2005 {published data only} Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers own milk in the feeding of extremely premature infants. Pediatrics 2005;116:4006. Schultz 1980 {published data only} Schultz K, Soltesz G, Mestyan J. The metabolic consequences of human milk and formula feeding in premature infants. Acta Paediatrica 1980;69:64752. Tyson 1983 {published data only} Tyson JE, Lasky RE, Mize CE, Richards CJ, Blair SN, Whyte R, et al.Growth, metabolic response, and development in very-low-birthweight infants fed banked human milk or enriched formula. I. Neonatal ndings. Journal of Pediatrics 1983;103:95104.
References to studies excluded from this review

10
Cooper 1984 {published data only} Cooper PA, Rothberg AD, Pettifor JM, Bolton KD, Devenhuis S. Growth and biochemical response of premature infants fed pooled preterm milk or special formula. Journal of Pediatric Gastroenterology and Nutrition 1984;3:74954. Jarvenpaa 1983 {published data only} Jarvenpaa AL, Raiha NC, Rassin DK, Gaull GE. Feeding the lowbirth-weight infant: I. Taurine and cholesterol supplementation of formula does not affect growth and metabolism. Pediatrics 1983;71: 1718. Narayanan 1982 {published data only} Narayanan I, Prakash K, Gujral VV. The value of human milk in the prevention of infection in the high-risk low-birth-weight infant. Journal of Pediatrics 1981;99:4968. Narayanan I, Prakash K, Prabhakar AK, Gujral VV. A planned prospective evaluation of the anti-infective property of varying quantities of expressed human milk. Acta Paediatrica 1982;71:4415. OConnor 2003 {published data only} OConnor DL, Jacobs J, Hall R, Adamkin D, Auestad N, Castillo M, et al.Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. Journal of Pediatric Gastroenterology and Nutrition 2003;37:43746. Putet 1984 {published data only} Putet G, Senterre J, Rigo J, Salle B. Nutrient balance, energy utilization, and composition of weight gain in very-low-birth-weight infants fed pooled human milk or a preterm formula. Journal of Pediatrics 1984;105:7985. Svenningsen 1982 {published data only} Svenningsen NW, Lindroth M, Lindquist B. Growth in relation to protein intake of low birth weight infants. Early Human Development 1982;6:4758.
Fewtrell 1999 Fewtrell M, Lucas A. Nutritional physiology: dietary requirements of term and preterm infants. In: Rennie JM, Roberton NRC editor (s). Textbook of Neonatology. 3rd Edition. Edinburgh: Churchill Livingstone, 1999:30525. Foster 2001 Foster J, Cole M. Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth weight neonates. Cochrane Database of Systematic Reviews 2001, Issue 3.[Art. No.: CD001816. DOI: 10.1002/14651858.CD001816.pub2] Gross 1980 Gross SJ, David RJ, Bauman L, Tomarelli RM. Nurtitional composition of milk produced by mothers delivering preterm. Journal of Pediatrics 1980;96:6414. Gross 1981 Gross SJ, Buckley RH, Wakil SS, McAllister DC, David RJ, Faix RG. Elevated IgA concentration in milk produced by mothers delivered of preterm infants. Journal of Pediatrics 1981;99:38993. Hay 1994 Hay WW Jr. Nutritional requirements of extremely low birthweight infants. Acta Paediatrica 1994;402:949. Kuschel 1999 Kuschel CA, Harding JE. Carbohydrate supplementation of human milk to promote growth in preterm infants (Cochrane Review). Cochrane Database of Systematic Reviews 1999, Issue 2.[Art. No.: CD000280. DOI: 10.1002/14651858.CD000280] Kuschel 2000a Kuschel CA, Harding JE. Protein supplementation of human milk for promoting growth in preterm infants (Cochrane Review). Cochrane Database of Systematic Reviews 2000, Issue 2.[Art. No.: CD000433. DOI: 10.1002/14651858.CD000433] Kuschel 2000b Kuschel CA, Harding JE. Fat supplementation of human milk for promoting growth in preterm infants (Cochrane Review). Cochrane Database of Systematic Reviews 2002, Issue 2.[Art. No.: CD000341. DOI: 10.1002/14651858.CD000341] Kuschel 2004 Kuschel CA, Harding JE. Multicomponent fortied human milk for promoting growth in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 1.[Art. No.: CD000343. DOI: 10.1002/14651858.CD000343.pub2] Lucas 1978 Lucas A, Gibbs JH, Baum JD. The biology of drip breast milk. Early Human Development 1978;2/4:35161. Lucas 1990 Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:151923. Lucas 1992 Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breast milk and subsequent intelligence quotient in children born preterm. Lancet 1992;339:2614. Morley 1988 Morley R, Cole TJ, Powell R, Lucas A. Mothers choice to provide breast milk and developmental outcome. Archives of Disease in Childhood 1988;63:13821385.
11
Additional references
AAP 1997 American Academy of Pediatrics and Work Group on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 1997;100:1035 1039. Ameil-Tison 1986 Ameil-Tison C, Grenier G. Neurological assessment during the rst year of life. Oxford: Oxford University Press, 1986. Beeby 1992 Beeby PJ, Jeffrey H. Risk factors for necrotising enterocolitis: the inuence of gestational age. Archives of Disease in Childhood 1992; 67:4325. Dorling 2006 Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Archives of Disease in Childhood Fetal and Neonatal Edition 2005;90:F35963. Fairey 1997 Fairey AK, Butte NF, Mehta N, Thotathuchery M, Schanler RJ, Heird WC. Nutrient accretion in preterm infants fed formula with different protein:energy ratios. Journal of Pediatric Gastroenterology and Nutrition 1997;25:3745.
Schanler 1994 Schanler RJ, Rifka M. Calcium, phosphorus and magnesium needs for low birth weight infants. Acta Paediatrica 1994;405 (suppl): 1116. Schanler 1995 Schanler RJ. Suitability of human milk for the low-birthweight infant. Clinics in Perinatology 1995;22:20722. Tsang 1993 Tsang RC, Lucas A, Uauy R, Zlotkin S. Nutritional needs for the newborn infant. Scientic basis and practical guidelines. Pawling, New York: Caduceus Medical Publishers, 1993:2889. Wight 2001 Wight NE. Donor human milk for preterm infants. Journal of Perinatology 2001;21:24954.
References to other published versions of this review

Henderson 2004 Henderson G, Anthony MY, McGuire W. Formula milk versus term human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1. McGuire 2001a McGuire W, Anthony MY. Formula milk versus term human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Indicates the major publication for the study
12
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Davies 1977 Methods 1. Blinding of randomisation: Cant tell 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: No 68 preterm infants: 28-36 weeks in two strata. Exclusions: multiple births, congenital abnormalities and chromosomal disorders, congenital infection. Growth restricted infants (<5th percentile) may also have been excluded. Department of Child Health, University Hospital of Wales, Cardiff. 1972- 73. Term formula milk (N= 34 ) versus unfortied, Pasteurised donor breast milk (N= 34). Assigned from birth for 2 months. Rates of weight gain, increase in head circumference and length from birth until 1 month and from 1 month until 2 months. Infants of mothers who wished to breastfeed were initially given expressed breast milk if unable to feed naturally. There were only two such infants, their feeding group was not specied and the results for these infants are not presented separately in the paper. Given that this applies to only two out of 68 infants, we have included this study in the review.
Participants
Interventions
Outcomes
Notes
Risk of bias Item Allocation concealment? Gross 1983 Methods 1. Blinding of randomisation: Yes 2. Blinding of intervention: No 3. Complete follow up: No 4. Blinding of outcome measurement: Cant tell 67 preterm infants (27-33 weeks). Birth weight <1600g. Excluded if congenital anomaly or major disease. Dept of Pediatrics, Duke University, USA. 1980- 82. Authors judgement Unclear Description B - Unclear
Participants
13
Gross 1983
(Continued)
Interventions
Term formula milk (N= 26) versus unfortied, Pasteurised donor breast milk (N=41). Feeds were assigned until the infant reached a weight of 1800g or until withdrawn from the study because of feed intolerance or necrotising enterocolitis. Time to regain birth weight. Mean daily gain in weight, length and head circumference, from regaining birth weight until reaching 1800g. Data on adverse events can be determined although these were not primary end-points of the study. Although the report gave information on adverse outcomes, the seven affected infants were withdrawn from the study and not included in the analyses of growth rates. Therefore, growth data are reported for 20 infants in each arm of the trial.
Outcomes
Notes
Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate
Lucas 1984a Methods 1. Blinding of randomisation: Yes 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: Cant tell 159 infants of birth weight <1850g. Stratied by birth weight <1200g and 1201- 1850g. Infants with congenital abnormalities excluded. Infants with intra-uterine growth restriction not excluded. Study undertaken in the early 1980s in neonatal units in Anglia region of the UK. Preterm formula milk (N= 76) versus donor (mainly drip) breast milk (N= 83). The formula was intended to be delivered at 180 ml/kg/day versus the breast milk at 200 ml/kg/day. Feeds were assigned until the infant reached a weight of 2000 g or until discharge from the neonatal unit. Short term outcomes: Time to regain birth weight (62 infants). Rates of change in weight (58 infants), crown-heel length (26 infants) and head circumference (48 infants) from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 g. Incidence of necrotising enterocolitis- suspected and conrmed reported on complete cohort of 159 infants. Longer term outcomes: Validated neurological assessment at 18 months in 122 (85%) of surviving infants. Bayley mental development index and psychomotor development index at 18 months, corrected for preterm gestation, in 114 (94%) of surviving infants suitable for the assessment.
Participants
Interventions
Outcomes
14
Lucas 1984a
(Continued) Growth performance in surviving infants (weight, length and head circumference) at 9 months (110 infants), 18 months (136 infants), and 7.5- 8 years (130 infants) post term.
Notes
The rst interim report provided data on short term growth outcomes in a pre-dened subset of the total cohort recruited. Follow-up at 18 months was achieved for more than 80% of surviving infants. Developmental assessments (Bayley Psychomotor and Mental Development Indices) at 18 months post term were reported for 114 of the 159 children originally enrolled in the study. 16 children had died and 7 had been lost to follow-up. 12 surviving children had cerebral palsy affecting ne motor skills, and these children were not assessed. A further 10 children were not assessed due to severe visual or hearing impairment or because follow up data were obtained by telephone for geographical reasons.
Lucas 1984b Methods 1. Blinding of randomisation: Yes 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: Cant tell 343 infants of birth weight <1850 g. Stratied by birth weight <1200g and 1201- 1850g. Infants with congenital abnormalities excluded. Infants with intra-uterine growth restriction not excluded. Study undertaken in the early 1980s in neonatal units in Anglia region of the UK. Preterm formula milk (N= 173) versus banked donor breast milk (N= 170 ) as a supplement to the mothers own breast milk. Short term outcomes:Time to regain birth weight (132 infants). Rates of change in weight (115 infants), crown-heel length (45 infants) and head circumference (97 infants) from the point of regained birth weight until discharge from the neonatal unit or reaching a weight of 2000 g. Incidence of necrotising enterocolitis- suspected and conrmed reported on complete cohort of 343 infants. Longer term outcomes: Validated neurological assessment, at 18 months, in 278 (88%) of surviving infants. Bayley mental development index and psychomotor development index at 18 months, corrected for preterm gestation, in 273 (96%) of surviving infants suitable for the assessment. Growth performance in surviving infants (weight, length and head circumference) at 9 months (259 infants), 18 months (302 infants), and 7.5- 8 years (290 infants) post term.
Participants
Interventions
Outcomes
15
Lucas 1984b
(Continued)
Notes
The rst interim report provided data on short term growth outcomes in a pre-dened subset of the total cohort recruited. Developmental assessments (Bayley Psychomotor and Mental Development Indices) at 18 months post term were reported for 273 of 343 children originally enrolled in the study. 29 children had died and 12 lost to follow-up. 24 surviving children had cerebral palsy affecting ne motor skills, and these children were not assessed. A further 5 children were not assessed due to severe visual or hearing impairment or because follow up data were obtained by telephone for geographical reasons.
Raiha 1976 Methods 1. Blinding of randomisation: Yes (only for formula milk groups) 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: Cant tell 106 preterm infants of birth weight less than 2100g, but between 10th and 90th centiles for birth weight. Infants excluded if evidence of physical abnormality or obvious disease. Premature Unit, Helsinki University Childrens Hospital. 1972 to 1975. Term formula milk (N= 84) versus unfortied donor breast milk (N= 22). Feeds continued until a weight of 2.4 kg was attained or until infants were withdrawn from the study because of a medical complication. Time, from birth, to regain birth weight. Rate of weight change from birth and from point of regained birth weight. Allocation to the formula milks was undertaken using a random sequence of four numbers, but every fth infant was allocated to receive term human milk, so allocation concealment may have been sub-optimal. Donor breast milk was given at a 170 mL/kg/day, compared with formula at 150 mL/kg/day, in order to achieve equivalent calorie inputs. Donor breast milk fed infants were also given supplemental vitamins.
Participants
Interventions
Outcomes
Notes
Risk of bias Item Allocation concealment? Authors judgement Unclear Description B - Unclear
16
Schanler 2005 Methods 1. Blinding of randomisation: Yes 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: Cant tell 173 infants of gestational age less than 30 weeks, whose mothers intended to breastfeed but whose own milk became insufcient from birth until 90 days of age or hospital discharge. North Shore University Hospital, New York, USA. 2000 to 2003. Preterm formula milk (N= 81) versus unfortied donor breast milk (N=92) given as a supplement to maternal breast milk. Incidence of late-onset invasive infection and/or necrotising enterocolitis, duration of hospitalisation and growth during the study period (weight gain, head circumference increment, and length increment). Participating infants received small quantities (20 ml per kg per day) of their own mothers milk during the rst week after birth and continued for 3-5 days before the volume was advanced. Milk intake was increased by 20 ml per kg per day to 100 ml per kg at which time human milk fortier was added. Subsequently the volume of fortied human milk was advanced by 20 m//kg per day until 160 mL/kg per day was achieved. If no mothers milk was available and the baby was assigned to donor breast milk then a similar advancement and fortication protocol was followed. For all infants, adjustments in milk intake between 160 and 200 mL/kg per day were recommended to ensure an average weekly weight gain of at least 15 g/kg per day. 17 enrolled infants were switched from donor breast milk to preterm formula because of poor weight gain but all of the analyses were by intention to treat. However, 7 infants who were never fed (3 in the donor milk group, 4 in the formula group) were excluded from the analyses.
Participants
Interventions
Outcomes
Notes
Schultz 1980 Methods 1. Blinding of randomisation: Cant tell 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: Cant tell 20 preterm or low birth weight infants; all infants to be physically normal with no further signs of disease; no further details published. Department of Paediatrics, University Medical School, Pecs, Hungary, prior to 1980.
Participants
17
Schultz 1980
(Continued)
Interventions Outcomes
Term formula milk (N= 10) versus donor breast milk (N= 10) for at least four weeks from birth. Time, from birth, to regain birth weight (mean but no standard deviation reported). Mean weight change from birth and from regaining birth weight calculable from graph but no SD.
Notes Risk of bias Item Allocation concealment? Tyson 1983 Methods 1. Blinding of randomisation: Yes 2. Blinding of intervention: No 3. Complete follow up: Yes 4. Blinding of outcome measurement: Cant tell for growth assessments, yes for Brazelton score. 81 very low birth weight infants, excluding infants with any signicant illness or those who required ventilatory support at day 10. Parklands memorial Hospital, Dallas, USA. Early 1980s. Preterm formula milk (N= 44) versus donor breast milk (N= 37). The donor breast milk was not Pasteurised. Feeds were allocated on the tenth day of life, and continued until the infant reached a weight of 2000 g or until withdrawn from the study because of any illness requiring intravenous infusion of fat or protein. Mean daily rates of change in weight, crown-heel length and head circumference from the tenth until the thirtieth day of life were reported. The feeds were not allocated until the tenth day after birth in order to avoid the use of protein-enriched formula when active growth was unlikely. In the rst nine days of life the infants received a term formula or maternal expressed breast milk (if available). Although the report gave information on adverse outcomes, including necrotising enterocolitis, the ve affected infants were withdrawn from the study and not included in the analyses of growth rates. Authors judgement Unclear Description B - Unclear
Participants
Interventions
Outcomes
Notes
18
Characteristics of excluded studies [ordered by study ID]
Cooper 1984
Cooper 1984 measured growth and adverse events in preterm infants fed preterm formula or donor breast milk, but for most participants the feeding group was not allocated randomly. Jarvenpaa 1983 compared growth in low birth weight infants fed formula verus breast milk. However, the allocation was not random since those infants whose mothers chose to provide their own milk were selectively assigned to the human milk group. Narayanan 1982 reported a block randomised trial in low birth weight infants of feeding with formula milk versus expressed human milk, the latter being a mixture of preterm and term human milk. The randomised blocked design was followed strictly at rst, but in the second year, many of the low birth weight infants were allocated to one of the human milk groups (rather than the formula group). Hence, the data for year 1 are completely random (all 4 groups can be compared and be included in our review), but the data for year 2 (and beyond) were not completely random (and should not be included). The authors reported that the results in the random and non-random phases were similar and therefore presented the combined results. The authors have been contacted to see if the results for year 1 are available separately. OConnor 2003 compared growth, feeding tolerance, morbidity and development in 463 low birth weight infants fed human milk or formula. However, the feeding groups were not randomly allocated. Although not clearly stated in the title or abstract, feeds do not appear to have been randomly assigned. Svenningsen 1982 randomly assigned 48 low birth weight infants to formula milk versus breast milk. However, most infants in the breast milk group received their own mothers expressed milk rather than donor breast milk.
Jarvenpaa 1983
Narayanan 1982
OConnor 2003
Putet 1984 Svenningsen 1982
19
DATA AND ANALYSES
Comparison 1. Formula milk versus donor breast milk
Outcome or subgroup title 1 Time to regain birth weight (days from birth) 2 Short term weight change (g/kg/ day) 3 Short term change in crown-heel length (mm/week) 4 Short term change in crownrump length (mm/week) 5 Short term change in femoral length (mm/week) 6 Short term change in head circumference (mm/week) 7 Weight (kg) at 9 months post term 8 Length (cm) at 9 months post term 9 Head circumference (cm) at 9 months post term 10 Weight (kg) at 18 months post term 11 Length (cm) at 18 months post term 12 Head circumference (cm) at 18 months post term 13 Weight (kg) at 7.5-8 years of age 14 Length (cm) at 7.5-8 years of age 15 Head circumference (cm) at 7.5-8 years of age 16 Bayley mental development index at 18 months 17 Bayley psychomotor development index at 18 months 18 Neurological impairment at 18 months 19 Mortality 20 Necrotising enterocolitis 21 Suspected necrotising enterocolitis 22 Feed intolerance or diarrhoea
No. of studies 2 7 6 1 1 6 2 2 2 2 2 2 2 2 2 2 2
No. of participants 166 649 441 106 106 515 369 369 369 438 438 438 420 420 420 387 387
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
Effect size -2.00 [-5.81, -2.18] 2.59 [1.99, 3.20] 1.14 [0.61, 1.67] 0.59 [0.08, 1.10] 0.34 [0.13, 0.55] 1.25 [0.75, 1.75] -0.03 [-0.26, 0.21] 0.03 [-0.64, 0.70] 0.20 [-0.13, 0.53] 0.10 [-0.15, 0.35] 0.53 [-0.15, 1.20] 0.10 [-0.19, 0.39] -0.56 [-1.42, 0.29] 0.05 [-1.12, 1.23] -0.19 [-0.54, 0.16] 1.24 [-2.62, 5.09] -0.32 [-3.43, 2.79]
2 3 5 3 2
400 668 816 583 148
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
1.21 [0.62, 2.35] 1.23 [0.72, 2.11] 2.46 [1.19, 5.08] 1.41 [0.73, 2.71] 4.92 [1.17, 20.70]
20
23 Incidence of invasive infection
166
Risk Ratio (M-H, Fixed, 95% CI)
0.98 [0.66, 1.44]
Comparison 2. Term formula versus donor breast milk
Outcome or subgroup title 1 Short term weight change (g/kg/ day) 2 Short term change in crown-heel length (mm/week) 3 Short term change in head circumference (mm/week) 4 Necrotising enterocolitis 5 Feed intolerance or diarrhoea
No. of studies 3 2 2 1 1
No. of participants 234 128 128 67 67
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 1.74 [0.96, 2.53] 0.80 [0.10, 1.50] 0.81 [0.15, 1.47] 4.73 [0.52, 43.09] 9.46 [1.21, 74.17]
Comparison 3. Preterm formula versus donor breast milk
Outcome or subgroup title 1 Short term weight change (g/kg/ day) 2 Short term change in crown-heel length (mm/week) 3 Short term change in head circumference (mm/week) 4 Necrotising enterocolitis 5 Feed intolerance or diarrhoea
No. of studies 4 4 4 4 1
No. of participants 415 313 387 749 81
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 3.83 [2.88, 4.78] 1.61 [0.79, 2.42] 1.84 [1.07, 2.61] 2.26 [1.04, 4.90] 1.68 [0.16, 17.82]
Comparison 4. Formula milk given as a sole diet versus donor breast milk given as a sole diet
Outcome or subgroup title 1 Short term weight change (g/kg/ day) 2 Short term change in crown-heel length (mm/week) 3 Short term change in head circumference (mm/week) 4 Necrotising enterocolitis
No. of studies 5 4 4 3
No. of participants 368 230 252 307
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 2.68 [1.96, 3.41] 1.28 [0.66, 1.90] 1.45 [0.88, 2.02] 4.05 [1.02, 16.18]
21
Comparison 5. Formula milk versus donor breast milk given as a supplement to maternal breast milk
Outcome or subgroup title 1 Short term weight change (g/kg/ day) 2 Short term change in crown-heel length (mm/week) 3 Short term change in head circumference (mm/week) 4 Mortality 5 Necrotising enterocolitis 6 Suspected necrotising enterocolitis
No. of studies 2 2 2 2 2 1
No. of participants 281 211 263 509 509 343
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 2.39 [1.28, 3.50] 0.75 [-0.28, 1.78] 0.59 [-0.44, 1.62] 1.16 [0.60, 2.24] 1.96 [0.82, 4.67] 1.07 [0.49, 2.36]
Analysis 1.1. Comparison 1 Formula milk versus donor breast milk, Outcome 1 Time to regain birth weight (days from birth).
Review: Formula milk versus donor breast milk for feeding preterm or low birth weight infants
Comparison: 1 Formula milk versus donor breast milk Outcome: 1 Time to regain birth weight (days from birth)
Study or subgroup
Formula milk N Mean(SD) 20 84 10.3 (3.6) 13.5 (5.3)
Donor breast milk N 40 22 Mean(SD) 15.1 (5.6) 16.3 (6.3)
Mean Difference IV,Fixed,95% CI
Weight
Gross 1983 Raiha 1976
59.9 % 40.1 %
-4.80 [ -7.15, -2.45 ] -2.80 [ -5.67, 0.07 ]
Total (95% CI)
104
62
100.0 % -4.00 [ -5.81, -2.18 ]
Heterogeneity: Chi2 = 1.12, df = 1 (P = 0.29); I2 =11% Test for overall effect: Z = 4.32 (P = 0.000016)
-4
-2
Favours formula milk
Favours breast milk
22
Analysis 1.2. Comparison 1 Formula milk versus donor breast milk, Outcome 2 Short term weight change (g/kg/day).
Comparison: 1 Formula milk versus donor breast milk Outcome: 2 Short term weight change (g/kg/day)
Study or subgroup
Formula milk N Mean(SD) 34 20 30 56 84 88 42 14.7 (4.7) 20.4 (2.7) 18 (6) 16.3 (4.5) 13.8 (2.5) 20.1 (6.7) 24.3 (8.2)
Donor breast milk N 34 40 28 59 22 78 34 Mean(SD) 13 (5.4) 14.9 (3.2) 12.8 (2.6) 14.3 (3.1) 13.6 (2) 17.1 (5) 12.4 (4.8)
Weight
Davies 1977 Gross 1983 Lucas 1984a Lucas 1984b Raiha 1976 Schanler 2005 Tyson 1983
6.4 % 15.5 % 6.7 % 18.3 % 37.5 % 11.6 % 4.2 %
1.70 [ -0.71, 4.11 ] 5.50 [ 3.96, 7.04 ] 5.20 [ 2.85, 7.55 ] 2.00 [ 0.58, 3.42 ] 0.20 [ -0.79, 1.19 ] 3.00 [ 1.21, 4.79 ] 11.90 [ 8.94, 14.86 ]
Total (95% CI)
354
295
100.0 % 2.59 [ 1.99, 3.20 ]
Heterogeneity: Chi2 = 80.10, df = 6 (P<0.00001); I2 =93% Test for overall effect: Z = 8.37 (P < 0.00001)
-10
-5
10
Favours breast milk
23
Analysis 1.3. Comparison 1 Formula milk versus donor breast milk, Outcome 3 Short term change in crown-heel length (mm/week).
Comparison: 1 Formula milk versus donor breast milk Outcome: 3 Short term change in crown-heel length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 34 20 12 20 88 42 9.3 (2) 7.2 (1.8) 9.7 (2.2) 9.6 (2.2) 10 (10) 11 (4)
Donor breast milk N 34 40 14 25 78 34 Mean(SD) 8.5 (2.4) 6.4 (1.6) 7.3 (2.4) 8.4 (1.4) 12 (8) 7 (5)
Weight
Davies 1977 Gross 1983 Lucas 1984a Lucas 1984b Schanler 2005 Tyson 1983
25.5 % 32.4 % 9.0 % 22.8 % 3.7 % 6.6 %
0.80 [ -0.25, 1.85 ] 0.80 [ -0.13, 1.73 ] 2.40 [ 0.63, 4.17 ] 1.20 [ 0.09, 2.31 ] -2.00 [ -4.74, 0.74 ] 4.00 [ 1.93, 6.07 ]
Total (95% CI)
216
225
100.0 % 1.14 [ 0.61, 1.67 ]
-10
-5
10
Favours breast milk
Analysis 1.4. Comparison 1 Formula milk versus donor breast milk, Outcome 4 Short term change in crown-rump length (mm/week).
Comparison: 1 Formula milk versus donor breast milk Outcome: 4 Short term change in crown-rump length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 84 5.34 (1.81)
Donor breast milk N 22 Mean(SD) 4.75 (0.81)
Weight
Raiha 1976
100.0 %
0.59 [ 0.08, 1.10 ]
Total (95% CI)

Heterogeneity: not applicable
84
22
100.0 % 0.59 [ 0.08, 1.10 ]
Test for overall effect: Z = 2.25 (P = 0.025)
-4
-2
Favours breast milk
24
Analysis 1.5. Comparison 1 Formula milk versus donor breast milk, Outcome 5 Short term change in femoral length (mm/week).
Comparison: 1 Formula milk versus donor breast milk Outcome: 5 Short term change in femoral length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 84 1.97 (0.46)
Donor breast milk N 22 Mean(SD) 1.63 (0.44)
Weight
Raiha 1976
100.0 %
0.34 [ 0.13, 0.55 ]
Total (95% CI)

84
22
100.0 % 0.34 [ 0.13, 0.55 ]
Test for overall effect: Z = 3.20 (P = 0.0014)
-1
-0.5
0.5
Favours breast milk
Analysis 1.6. Comparison 1 Formula milk versus donor breast milk, Outcome 6 Short term change in head circumference (mm/week).
Comparison: 1 Formula milk versus donor breast milk Outcome: 6 Short term change in head circumference (mm/week)
Study or subgroup
Formula milk N Mean(SD) 34 20 25 43 88 42 7.4 (1.6) 8.8 (2.2) 11 (3.6) 10.1 (2.9) 9 (8) 12 (2)
Donor breast milk N 34 40 23 54 78 34 Mean(SD) 6.8 (2) 7.7 (1.1) 8.6 (2.7) 9.4 (2.7) 9 (9) 8 (4)
Weight
Davies 1977 Gross 1983 Lucas 1984a Lucas 1984b Schanler 2005 Tyson 1983
33.6 % 23.8 % 7.8 % 19.6 % 3.7 % 11.5 %
0.60 [ -0.26, 1.46 ] 1.10 [ 0.08, 2.12 ] 2.40 [ 0.61, 4.19 ] 0.70 [ -0.43, 1.83 ] 0.0 [ -2.60, 2.60 ] 4.00 [ 2.53, 5.47 ]
Total (95% CI)
252
263
100.0 % 1.25 [ 0.75, 1.75 ]
Heterogeneity: Chi2 = 19.02, df = 5 (P = 0.002); I2 =74% Test for overall effect: Z = 4.89 (P < 0.00001)
-10
-5
10
Favours breast milk
25
Analysis 1.7. Comparison 1 Formula milk versus donor breast milk, Outcome 7 Weight (kg) at 9 months post term.
Comparison: 1 Formula milk versus donor breast milk Outcome: 7 Weight (kg) at 9 months post term
Study or subgroup
Donor breast milk N 62 133 Mean(SD) 7.7 (1.2) 8 (1.1)
Weight
Lucas 1984a Lucas 1984b
24.2 % 75.8 %
0.20 [ -0.27, 0.67 ] -0.10 [ -0.37, 0.17 ]
Total (95% CI)
174
195
100.0 % -0.03 [ -0.26, 0.21 ]
-1
-0.5
0.5
Favours breast milk
Analysis 1.8. Comparison 1 Formula milk versus donor breast milk, Outcome 8 Length (cm) at 9 months post term.
Comparison: 1 Formula milk versus donor breast milk Outcome: 8 Length (cm) at 9 months post term
Study or subgroup
Weight
25.6 % 74.4 %
0.40 [ -0.93, 1.73 ] -0.10 [ -0.88, 0.68 ]
Total (95% CI)
174
195
100.0 % 0.03 [ -0.64, 0.70 ]
Heterogeneity: Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0% Test for overall effect: Z = 0.08 (P = 0.94)
-4
-2
Favours breast milk
26
Analysis 1.9. Comparison 1 Formula milk versus donor breast milk, Outcome 9 Head circumference (cm) at 9 months post term.
Comparison: 1 Formula milk versus donor breast milk Outcome: 9 Head circumference (cm) at 9 months post term
Study or subgroup
Weight
25.5 % 74.5 %
0.20 [ -0.45, 0.85 ] 0.20 [ -0.18, 0.58 ]
Total (95% CI)
174
195
100.0 % 0.20 [ -0.13, 0.53 ]
-1
-0.5
0.5
Favours breast milk
Analysis 1.10. Comparison 1 Formula milk versus donor breast milk, Outcome 10 Weight (kg) at 18 months post term.
Comparison: 1 Formula milk versus donor breast milk Outcome: 10 Weight (kg) at 18 months post term
Study or subgroup
Formula milk N Mean(SD) 64 153 10 (1.3) 10.1 (1.3)
Weight
28.0 % 72.0 %
0.10 [ -0.37, 0.57 ] 0.10 [ -0.19, 0.39 ]
Total (95% CI)
217
221
100.0 % 0.10 [ -0.15, 0.35 ]
-1
-0.5
0.5
Favours breast milk
27
Analysis 1.11. Comparison 1 Formula milk versus donor breast milk, Outcome 11 Length (cm) at 18 months post term.
Comparison: 1 Formula milk versus donor breast milk Outcome: 11 Length (cm) at 18 months post term
Study or subgroup
Weight
27.7 % 72.3 %
0.60 [ -0.68, 1.88 ] 0.50 [ -0.29, 1.29 ]
Total (95% CI)
217
221
100.0 % 0.53 [ -0.15, 1.20 ]
-4
-2
Favours breast milk
Analysis 1.12. Comparison 1 Formula milk versus donor breast milk, Outcome 12 Head circumference (cm) at 18 months post term.
Comparison: 1 Formula milk versus donor breast milk Outcome: 12 Head circumference (cm) at 18 months post term
Study or subgroup
Weight
29.7 % 70.3 %
0.10 [ -0.44, 0.64 ] 0.10 [ -0.25, 0.45 ]
Total (95% CI)
217
221
100.0 % 0.10 [ -0.19, 0.39 ]
-1
-0.5
0.5
Favours breast milk
28
Analysis 1.13. Comparison 1 Formula milk versus donor breast milk, Outcome 13 Weight (kg) at 7.5-8 years of age.
Comparison: 1 Formula milk versus donor breast milk Outcome: 13 Weight (kg) at 7.5-8 years of age
Study or subgroup
Donor breast milk N 68 139 Mean(SD) 21.8 (5) 23.2 (4.8)
Weight
24.2 % 75.8 %
0.50 [ -1.24, 2.24 ] -0.90 [ -1.88, 0.08 ]
Total (95% CI)
213
207
100.0 % -0.56 [ -1.42, 0.29 ]
-4
-2
Favours breast milk
Analysis 1.14. Comparison 1 Formula milk versus donor breast milk, Outcome 14 Length (cm) at 7.5-8 years of age.
Comparison: 1 Formula milk versus donor breast milk Outcome: 14 Length (cm) at 7.5-8 years of age
Study or subgroup
Weight
27.3 % 72.7 %
1.00 [ -1.26, 3.26 ] -0.30 [ -1.68, 1.08 ]
Total (95% CI)
213
207
100.0 % 0.05 [ -1.12, 1.23 ]
-4
-2
Favours breast milk
29
Analysis 1.15. Comparison 1 Formula milk versus donor breast milk, Outcome 15 Head circumference (cm) at 7.5-8 years of age.
Comparison: 1 Formula milk versus donor breast milk Outcome: 15 Head circumference (cm) at 7.5-8 years of age
Study or subgroup
Weight
28.2 % 71.8 %
0.10 [ -0.56, 0.76 ] -0.30 [ -0.71, 0.11 ]
Total (95% CI)
213
207
100.0 % -0.19 [ -0.54, 0.16 ]
-1
-0.5
0.5
Favours breast milk
Favours formual milk
Analysis 1.16. Comparison 1 Formula milk versus donor breast milk, Outcome 16 Bayley mental development index at 18 months.
Comparison: 1 Formula milk versus donor breast milk Outcome: 16 Bayley mental development index at 18 months
Study or subgroup
Formula milk N Mean(SD) 52 139 95.3 (19.5) 103.8 (20)
Weight
33.0 % 67.0 %
0.50 [ -6.21, 7.21 ] 1.60 [ -3.11, 6.31 ]
Total (95% CI)
191
196
100.0 % 1.24 [ -2.62, 5.09 ]
-10
-5
10
Favours breast milk
30
Analysis 1.17. Comparison 1 Formula milk versus donor breast milk, Outcome 17 Bayley psychomotor development index at 18 months.
Comparison: 1 Formula milk versus donor breast milk Outcome: 17 Bayley psychomotor development index at 18 months
Study or subgroup
Donor breast milk N 62 134 Mean(SD) 93 (14.2) 95.5 (15)
Weight
31.0 % 69.0 %
1.20 [ -4.38, 6.78 ] -1.00 [ -4.74, 2.74 ]
Total (95% CI)
191
196
100.0 % -0.32 [ -3.43, 2.79 ]
-10
-5
10
Favours breast milk
Analysis 1.18. Comparison 1 Formula milk versus donor breast milk, Outcome 18 Neurological impairment at 18 months.
Comparison: 1 Formula milk versus donor breast milk Outcome: 18 Neurological impairment at 18 months
Study or subgroup
Formula milk n/N
Donor breast milk n/N 4/66 11/140
Risk Ratio M-H,Fixed,95% CI
Weight
7/56 10/138
25.2 % 74.8 %
2.06 [ 0.64, 6.68 ] 0.92 [ 0.40, 2.10 ]
Total (95% CI)
194
206
100.0 %
1.21 [ 0.62, 2.35 ]
Total events: 17 (Formula milk), 15 (Donor breast milk) Heterogeneity: Chi2 = 1.21, df = 1 (P = 0.27); I2 =17% Test for overall effect: Z = 0.56 (P = 0.57)
0.1 0.2
0.5 1.0 2.0
5.0 10.0
Favours breast milk
31
Analysis 1.19. Comparison 1 Formula milk versus donor breast milk, Outcome 19 Mortality.
Comparison: 1 Formula milk versus donor breast milk Outcome: 19 Mortality
Study or subgroup
Formula milk n/N
Donor breast milk n/N 7/83 12/170 3/78
Weight
Lucas 1984a Lucas 1984b Schanler 2005
9/76 15/173 3/88
30.4 % 55.1 % 14.5 %
1.40 [ 0.55, 3.59 ] 1.23 [ 0.59, 2.55 ] 0.89 [ 0.18, 4.26 ]
Total (95% CI)
337
331
100.0 %
1.23 [ 0.72, 2.11 ]
Total events: 27 (Formula milk), 22 (Donor breast milk) Heterogeneity: Chi2 = 0.24, df = 2 (P = 0.89); I2 =0.0% Test for overall effect: Z = 0.76 (P = 0.45)
0.1 0.2
0.5 1.0 2.0
5.0 10.0
Favours formula
Favours breast milk
Analysis 1.20. Comparison 1 Formula milk versus donor breast milk, Outcome 20 Necrotising enterocolitis.
Comparison: 1 Formula milk versus donor breast milk Outcome: 20 Necrotising enterocolitis
Study or subgroup
Formula milk n/N
Donor breast milk n/N 1/41 1/83 2/170 5/78 0/37
Weight
Gross 1983 Lucas 1984a Lucas 1984b Schanler 2005 Tyson 1983
3/26 4/76 5/173 10/88 1/44
8.1 % 10.0 % 21.0 % 55.3 % 5.7 %
4.73 [ 0.52, 43.09 ] 4.37 [ 0.50, 38.23 ] 2.46 [ 0.48, 12.49 ] 1.77 [ 0.63, 4.96 ] 2.53 [ 0.11, 60.39 ]
Total (95% CI)
407
409
100.0 %
2.46 [ 1.19, 5.08 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
32
Analysis 1.21. Comparison 1 Formula milk versus donor breast milk, Outcome 21 Suspected necrotising enterocolitis.
Comparison: 1 Formula milk versus donor breast milk Outcome: 21 Suspected necrotising enterocolitis
Study or subgroup
Formula milk n/N
Weight
Lucas 1984a Lucas 1984b Tyson 1983
6/76 12/173 2/44
19.8 % 76.5 % 3.7 %
2.18 [ 0.57, 8.43 ] 1.07 [ 0.49, 2.36 ] 4.22 [ 0.21, 85.27 ]
Total (95% CI)
293
290
100.0 %
1.41 [ 0.73, 2.71 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
Analysis 1.22. Comparison 1 Formula milk versus donor breast milk, Outcome 22 Feed intolerance or diarrhoea.
Comparison: 1 Formula milk versus donor breast milk Outcome: 22 Feed intolerance or diarrhoea
Study or subgroup
Formula milk n/N
Weight
Gross 1983 Tyson 1983
6/26 2/44
41.7 % 58.3 %
9.46 [ 1.21, 74.17 ] 1.68 [ 0.16, 17.82 ]
Total (95% CI)
70
78
100.0 %
4.92 [ 1.17, 20.70 ]
Total events: 8 (Formula milk), 2 (Donor breast milk) Heterogeneity: Chi2 = 1.18, df = 1 (P = 0.28); I2 =15% Test for overall effect: Z = 2.18 (P = 0.030)
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
33
Analysis 1.23. Comparison 1 Formula milk versus donor breast milk, Outcome 23 Incidence of invasive infection.
Comparison: 1 Formula milk versus donor breast milk Outcome: 23 Incidence of invasive infection
Study or subgroup
Formula milk n/N
Donor breast milk n/N 30/78
Weight
Schanler 2005
33/88
100.0 %
0.98 [ 0.66, 1.44 ]
Total (95% CI)

88
78
100.0 %
0.98 [ 0.66, 1.44 ]
Total events: 33 (Formula milk), 30 (Donor breast milk) Test for overall effect: Z = 0.13 (P = 0.90)
0.5
0.7
1.0
1.5
2.0
Favours formula
Favours breast milk
Analysis 2.1. Comparison 2 Term formula versus donor breast milk, Outcome 1 Short term weight change (g/kg/day).
Comparison: 2 Term formula versus donor breast milk Outcome: 1 Short term weight change (g/kg/day)
Study or subgroup
Formula milk N Mean(SD) 34 20 84 14.7 (4.7) 20.4 (2.7) 13.8 (2.5)
Donor breast milk N 34 40 22 Mean(SD) 13 (5.4) 14.9 (3.2) 13.6 (2)
Weight
Davies 1977 Gross 1983 Raiha 1976
10.7 % 26.1 % 63.2 %
1.70 [ -0.71, 4.11 ] 5.50 [ 3.96, 7.04 ] 0.20 [ -0.79, 1.19 ]
Total (95% CI)
138
96
100.0 % 1.74 [ 0.96, 2.53 ]
Heterogeneity: Chi2 = 32.04, df = 2 (P<0.00001); I2 =94% Test for overall effect: Z = 4.33 (P = 0.000015)
-10
-5
10
Favours breast milk
34
Analysis 2.2. Comparison 2 Term formula versus donor breast milk, Outcome 2 Short term change in crown-heel length (mm/week).
Comparison: 2 Term formula versus donor breast milk Outcome: 2 Short term change in crown-heel length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 34 20 9.3 (2) 7.2 (1.8)
Weight
Davies 1977 Gross 1983
44.0 % 56.0 %
0.80 [ -0.25, 1.85 ] 0.80 [ -0.13, 1.73 ]
Total (95% CI)
54
74
100.0 % 0.80 [ 0.10, 1.50 ]
-4
-2
Favours breast milk
Analysis 2.3. Comparison 2 Term formula versus donor breast milk, Outcome 3 Short term change in head circumference (mm/week).
Comparison: 2 Term formula versus donor breast milk Outcome: 3 Short term change in head circumference (mm/week)
Study or subgroup
Donor breast milk N 34 40 Mean(SD) 6.8 (2) 7.7 (1.1)
Weight
Davies 1977 Gross 1983
58.5 % 41.5 %
0.60 [ -0.26, 1.46 ] 1.10 [ 0.08, 2.12 ]
Total (95% CI)
54
74
100.0 % 0.81 [ 0.15, 1.47 ]
-4
-2
Favours breast milk
35
Analysis 2.4. Comparison 2 Term formula versus donor breast milk, Outcome 4 Necrotising enterocolitis.
Comparison: 2 Term formula versus donor breast milk Outcome: 4 Necrotising enterocolitis
Study or subgroup
Formula milk n/N
Weight
Gross 1983
3/26
100.0 %
4.73 [ 0.52, 43.09 ]
Total (95% CI)

26
41
100.0 %
4.73 [ 0.52, 43.09 ]
0.01
0.1
1.0
10.0
100.0
Favours breast milk
Analysis 2.5. Comparison 2 Term formula versus donor breast milk, Outcome 5 Feed intolerance or diarrhoea.
Comparison: 2 Term formula versus donor breast milk Outcome: 5 Feed intolerance or diarrhoea
Study or subgroup
Formula milk n/N
Weight
Gross 1983
6/26
100.0 %
9.46 [ 1.21, 74.17 ]
Total (95% CI)

26
41
100.0 %
9.46 [ 1.21, 74.17 ]
0.01
0.1
1.0
10.0
100.0
Favours breast milk
36
Analysis 3.1. Comparison 3 Preterm formula versus donor breast milk, Outcome 1 Short term weight change (g/kg/day).
Comparison: 3 Preterm formula versus donor breast milk Outcome: 1 Short term weight change (g/kg/day)
Study or subgroup
Formula milk N Mean(SD) 30 56 88 42 18 (6) 16.3 (4.5) 20.1 (6.7) 24.3 (8.2)
Donor breast milk N 28 59 78 34 Mean(SD) 12.8 (2.6) 14.3 (3.1) 17.1 (5) 12.4 (4.8)
Weight
Lucas 1984a Lucas 1984b Schanler 2005 Tyson 1983
16.4 % 44.9 % 28.4 % 10.3 %
5.20 [ 2.85, 7.55 ] 2.00 [ 0.58, 3.42 ] 3.00 [ 1.21, 4.79 ] 11.90 [ 8.94, 14.86 ]
Total (95% CI)
216
199
100.0 % 3.83 [ 2.88, 4.78 ]
-100
-50
50
100
Favours breast milk
Analysis 3.2. Comparison 3 Preterm formula versus donor breast milk, Outcome 2 Short term change in crown-heel length (mm/week).
Comparison: 3 Preterm formula versus donor breast milk Outcome: 2 Short term change in crown-heel length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 12 20 88 42 9.7 (2.2) 9.6 (2.2) 10 (10) 11 (4)
Donor breast milk N 14 25 78 34 Mean(SD) 7.3 (2.4) 8.4 (1.4) 12 (8) 7 (5)
Weight
21.3 % 54.2 % 8.9 % 15.6 %
2.40 [ 0.63, 4.17 ] 1.20 [ 0.09, 2.31 ] -2.00 [ -4.74, 0.74 ] 4.00 [ 1.93, 6.07 ]
Total (95% CI)
162
151
100.0 % 1.61 [ 0.79, 2.42 ]
-10
-5
10
Favours breast milk
37
Analysis 3.3. Comparison 3 Preterm formula versus donor breast milk, Outcome 3 Short term change in head circumference (mm/week).
Comparison: 3 Preterm formula versus donor breast milk Outcome: 3 Short term change in head circumference (mm/week)
Study or subgroup
Formula milk N Mean(SD) 25 43 88 42 11 (3.6) 10.1 (2.9) 9 (8) 12 (2)
Donor breast milk N 23 54 78 34 Mean(SD) 8.6 (2.7) 9.4 (2.7) 9 (9) 8 (4)
Weight
18.3 % 46.1 % 8.6 % 27.0 %
2.40 [ 0.61, 4.19 ] 0.70 [ -0.43, 1.83 ] 0.0 [ -2.60, 2.60 ] 4.00 [ 2.53, 5.47 ]
Total (95% CI)
198
189
100.0 % 1.84 [ 1.07, 2.61 ]
-10
-5
10
Favours breast milk
Analysis 3.4. Comparison 3 Preterm formula versus donor breast milk, Outcome 4 Necrotising enterocolitis.
Comparison: 3 Preterm formula versus donor breast milk Outcome: 4 Necrotising enterocolitis
Study or subgroup
Formula milk n/N
Donor breast milk n/N 1/83 2/170 5/78 0/37
Weight
4/76 5/173 10/88 1/44
10.8 % 22.9 % 60.1 % 6.1 %
4.37 [ 0.50, 38.23 ] 2.46 [ 0.48, 12.49 ] 1.77 [ 0.63, 4.96 ] 2.53 [ 0.11, 60.39 ]
Total (95% CI)
381
368
100.0 %
2.26 [ 1.04, 4.90 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
38
Analysis 3.5. Comparison 3 Preterm formula versus donor breast milk, Outcome 5 Feed intolerance or diarrhoea.
Comparison: 3 Preterm formula versus donor breast milk Outcome: 5 Feed intolerance or diarrhoea
Study or subgroup
Formula milk n/N
Weight
Gross 1983
2/44
100.0 %
1.68 [ 0.16, 17.82 ]
Total (95% CI)

44
37
100.0 %
1.68 [ 0.16, 17.82 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
Analysis 4.1. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 1 Short term weight change (g/kg/day).
Comparison: 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet Outcome: 1 Short term weight change (g/kg/day)
Study or subgroup
Formula milk N Mean(SD) 34 20 30 84 42 14.7 (4.7) 20.4 (2.7) 18 (6) 13.8 (2.5) 24.3 (8.2)
Donor breast milk N 34 40 28 22 34 Mean(SD) 13 (5.4) 14.9 (3.2) 12.8 (2.6) 13.6 (2) 12.4 (4.8)
Weight
Davies 1977 Gross 1983 Lucas 1984a Raiha 1976 Tyson 1983
9.1 % 22.0 % 9.5 % 53.4 % 6.0 %
1.70 [ -0.71, 4.11 ] 5.50 [ 3.96, 7.04 ] 5.20 [ 2.85, 7.55 ] 0.20 [ -0.79, 1.19 ] 11.90 [ 8.94, 14.86 ]
Total (95% CI)
210
158
100.0 % 2.68 [ 1.96, 3.41 ]
-10
-5
10
Favours breast milk
Favours formula
39
Analysis 4.2. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 2 Short term change in crown-heel length (mm/week).
Comparison: 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet Outcome: 2 Short term change in crown-heel length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 34 20 12 42 9.3 (2) 7.2 (1.8) 9.7 (2.2) 11 (4)
Donor breast milk N 34 40 14 34 Mean(SD) 8.5 (2.4) 6.4 (1.6) 7.3 (2.4) 7 (5)
Weight
Davies 1977 Gross 1983 Lucas 1984a Tyson 1983
34.7 % 44.1 % 12.2 % 8.9 %
0.80 [ -0.25, 1.85 ] 0.80 [ -0.13, 1.73 ] 2.40 [ 0.63, 4.17 ] 4.00 [ 1.93, 6.07 ]
Total (95% CI)
108
122
100.0 % 1.28 [ 0.66, 1.90 ]
-10
-5
10
Favours formula
Favours breast milk
Analysis 4.3. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 3 Short term change in head circumference (mm/week).
Comparison: 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet Outcome: 3 Short term change in head circumference (mm/week)
Study or subgroup
Formula milk N Mean(SD) 34 20 25 42 7.4 (1.6) 8.8 (2.2) 11 (3.6) 12 (2)
Donor breast milk N 34 40 23 34 Mean(SD) 6.8 (2) 7.7 (1.1) 8.6 (2.7) 8 (4)
Weight
Davies 1977 Gross 1983 Lucas 1984a Tyson 1983
43.8 % 31.1 % 10.1 % 15.0 %
0.60 [ -0.26, 1.46 ] 1.10 [ 0.08, 2.12 ] 2.40 [ 0.61, 4.19 ] 4.00 [ 2.53, 5.47 ]
Total (95% CI)
121
131
100.0 % 1.45 [ 0.88, 2.02 ]
-10
-5
10
Favours breast milk
40
Analysis 4.4. Comparison 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet, Outcome 4 Necrotising enterocolitis.
Comparison: 4 Formula milk given as a sole diet versus donor breast milk given as a sole diet Outcome: 4 Necrotising enterocolitis
Study or subgroup
Formula milk n/N
Weight
Gross 1983 Lucas 1984a Tyson 1983
3/26 4/76 1/44
34.1 % 42.0 % 23.8 %
4.73 [ 0.52, 43.09 ] 4.37 [ 0.50, 38.23 ] 2.53 [ 0.11, 60.39 ]
Total (95% CI)
146
161
100.0 %
4.05 [ 1.02, 16.18 ]
0.0010
0.1
1.0 10.0
1000.0
Favours formula
Favours breast milk
Analysis 5.1. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 1 Short term weight change (g/kg/day).
Comparison: 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk Outcome: 1 Short term weight change (g/kg/day)
Study or subgroup
Donor breast milk N 59 78 Mean(SD) 14.3 (3.1) 17.1 (5)
Weight
Lucas 1984b Schanler 2005
61.3 % 38.7 %
2.00 [ 0.58, 3.42 ] 3.00 [ 1.21, 4.79 ]
Total (95% CI)
144
137
100.0 % 2.39 [ 1.28, 3.50 ]
-10
-5
10
Favours breast milk
41
Analysis 5.2. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 2 Short term change in crown-heel length (mm/week).
Comparison: 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk Outcome: 2 Short term change in crown-heel length (mm/week)
Study or subgroup
Formula milk N Mean(SD) 20 88 9.6 (2.2) 10 (10)
Donor breast milk N 25 78 Mean(SD) 8.4 (1.4) 12 (8)
Weight
85.9 % 14.1 %
1.20 [ 0.09, 2.31 ] -2.00 [ -4.74, 0.74 ]
Total (95% CI)
108
103
100.0 % 0.75 [ -0.28, 1.78 ]
-10
-5
10
Favours breast milk
Analysis 5.3. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 3 Short term change in head circumference (mm/week).
Comparison: 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk Outcome: 3 Short term change in head circumference (mm/week)
Study or subgroup
Formula milk N Mean(SD) 43 88 10.1 (2.9) 9 (8)
Donor breast milk N 54 78 Mean(SD) 9.4 (2.7) 9 (9)
Weight
84.2 % 15.8 %
0.70 [ -0.43, 1.83 ] 0.0 [ -2.60, 2.60 ]
Total (95% CI)
131
132
100.0 % 0.59 [ -0.44, 1.62 ]
-10
-5
10
Favours breast milk
42
Analysis 5.4. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 4 Mortality.
Comparison: 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk Outcome: 4 Mortality
Study or subgroup
Formula milk n/N
Weight
15/173 3/88
79.2 % 20.8 %
1.23 [ 0.59, 2.55 ] 0.89 [ 0.18, 4.26 ]
Total (95% CI)
261
248
100.0 %
1.16 [ 0.60, 2.24 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
Analysis 5.5. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 5 Necrotising enterocolitis.
Comparison: 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk Outcome: 5 Necrotising enterocolitis
Study or subgroup
Formula milk n/N
Weight
5/173 10/88
27.6 % 72.4 %
2.46 [ 0.48, 12.49 ] 1.77 [ 0.63, 4.96 ]
Total (95% CI)
261
248
100.0 %
1.96 [ 0.82, 4.67 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
43
Analysis 5.6. Comparison 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk, Outcome 6 Suspected necrotising enterocolitis.
Comparison: 5 Formula milk versus donor breast milk given as a supplement to maternal breast milk Outcome: 6 Suspected necrotising enterocolitis
Study or subgroup
Formula milk n/N
Weight
Lucas 1984b
12/173
100.0 %
1.07 [ 0.49, 2.36 ]
Total (95% CI)

173
170
100.0 %
1.07 [ 0.49, 2.36 ]
0.0010
0.1
1.0 10.0
1000.0
Favours breast milk
WHATS NEW
Last assessed as up-to-date: 17 June 2007.
6 June 2008
Amended
Converted to new review format.
HISTORY
Protocol rst published: Issue 1, 2001 Review rst published: Issue 4, 2001
44
18 June 2007
New search has been performed
This updates the review Formula milk versus term human milk for feeding preterm or low birth weight infants published in The Cochrane Library, Issue 1, 2004 (Henderson 2004). In this update, the structure of the review has been revised in the following manner: 1. Trials that compared feeding with formula milk with either term or preterm donor breast milk (previous review restricted to term breast milk). 2. Trials that compared feeding with formula versus donor breast milk as a sole diet or as a supplement to maternal expressed breast milk (previous review restricted to sole diet). This update includes one trial published since the previous update (Schlanler 2005), and one older trial that was not included in the previous review (Lucas 1984b). The major change to the review ndings is that the metaanalysis now detects a statistically signicantly higher rate of necrotising enterocolitis in the formula fed group.
18 June 2007
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
William McGuire (WM) and Mary Anthony developed the protocol and undertook the original review in 2000. Ginny Henderson and WM updated the review in 2003. Maria Quigley and WM revised the protocol and updated the review in 2007.
DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT Internal sources

ANU Medical School, Australia. National Perinatal Epidemiology Unit, UK.
45
External sources
Department of Health, UK. Royal College of Paediatrics and Child Health, UK. Tenovus, Scotland, UK.
INDEX TERMS Medical Subject Headings (MeSH)

Enteral Nutrition [ methods]; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant Formula; Infant Nutritional Physiological Phenomena; Milk, Human; Randomized Controlled Trials as Topic
MeSH check words

Humans
46

Formula Milk Versus Donor Breast Milk For Feeding Preterm or Low Birth Weight Infants (Review)

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Formula Milk Versus Donor Breast Milk For Feeding Preterm or Low Birth Weight Infants (Review)

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Formula milk versus donor breast milk for feeding preterm or low birth weight infants (Review)

Quigley M, Henderson G, Anthony MY, McGuire W

Criteria for considering studies for this review

Search methods for identication of studies

Data collection and analysis

Risk of bias in included studies

AUTHORS CONCLUSIONS Implications for practice

Implications for research

References to studies included in this review

References to studies excluded from this review

References to other published versions of this review

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Putet 1984 Svenningsen 1982

DATA AND ANALYSES

Comparison 1. Formula milk versus donor breast milk

400 668 816 583 148

23 Incidence of invasive infection

Risk Ratio (M-H, Fixed, 95% CI)

0.98 [0.66, 1.44]

Comparison 2. Term formula versus donor breast milk

No. of participants 234 128 128 67 67

Comparison 3. Preterm formula versus donor breast milk

No. of participants 415 313 387 749 81

No. of participants 368 230 252 307

No. of participants 281 211 263 509 509 343

Formula milk N Mean(SD) 20 84 10.3 (3.6) 13.5 (5.3)

Donor breast milk N 40 22 Mean(SD) 15.1 (5.6) 16.3 (6.3)

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

Gross 1983 Raiha 1976

-4.80 [ -7.15, -2.45 ] -2.80 [ -5.67, 0.07 ]

Total (95% CI)

100.0 % -4.00 [ -5.81, -2.18 ]

Favours formula milk

Favours breast milk

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

6.4 % 15.5 % 6.7 % 18.3 % 37.5 % 11.6 % 4.2 %

Total (95% CI)

100.0 % 2.59 [ 1.99, 3.20 ]

Favours breast milk

Favours formula milk

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

25.5 % 32.4 % 9.0 % 22.8 % 3.7 % 6.6 %

Total (95% CI)

100.0 % 1.14 [ 0.61, 1.67 ]

Favours breast milk

Favours formula milk

Formula milk N Mean(SD) 84 5.34 (1.81)

Donor breast milk N 22 Mean(SD) 4.75 (0.81)

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

0.59 [ 0.08, 1.10 ]

Total (95% CI)

100.0 % 0.59 [ 0.08, 1.10 ]

Test for overall effect: Z = 2.25 (P = 0.025)

Favours breast milk

Favours formula milk

Formula milk N Mean(SD) 84 1.97 (0.46)

Donor breast milk N 22 Mean(SD) 1.63 (0.44)